Aza hydroxylated ethyl amine compounds utility

ABSTRACT

Disclosed are compounds of formula:  
                 
 
     and pharmaceutically acceptable salts and esters thereof, useful in treating and/or preventing Alzheimer&#39;s disease and other similar diseases, wherein R N , R C , R 1 , R 2  and R 20  are defined herein,. These compounds include inhibitors of the beta-secretase enzyme that are useful in the treatment of Alzheimer&#39;s disease and other diseases characterized by deposition of A beta peptide in a mammal. The compounds of the invention are useful in pharmaceutical compositions and methods of treatment to reduce A beta peptide formation.

BACKGROUND OF THE INVENTION

[0001] 1. Field of the Invention

[0002] This invention relates to aza hydroxylated ethyl aminederivatives and more specifically to such compounds that are useful inthe treatment and/or prevention of Alzheimer's disease and similardiseases. More specifically the invention relates to substituted azahydroxy ethyl amines that are capable of inhibiting beta-secretase, anenzyme that cleaves amyloid precursor protein to produce amyloid betapeptide (A beta), a major component of the amyloid plaques found in thebrains of Alzheimer's sufferers.

[0003] 2. Description of Related Art

[0004] Alzheimer's disease (AD) is a progressive degenerative disease ofthe brain primarily associated with aging. Clinical presentation of ADis characterized by loss of memory, cognition, reasoning, judgment, andorientation. As the disease progresses, motor, sensory, and linguisticabilities are also affected until there is global impairment of multiplecognitive functions. These cognitive losses occur gradually, buttypically lead to severe impairment and eventual death in the range offour to twelve years.

[0005] Alzheimer's disease is characterized by two major pathologicobservations in the brain: neurofibrillary tangles and beta amyloid (orneuritic) plaques, comprised predominantly of an aggregate of a peptidefragment know as A beta. Individuals with AD exhibit characteristicbeta-amyloid deposits in the brain (beta amyloid plaques) and incerebral blood vessels (beta amyloid angiopathy) as well asneurofibrillary tangles. Neurofibrillary tangles occur not only inAlzheimer's disease but also in other dementia-inducing disorders. Onautopsy, large numbers of these lesions are generally found in areas ofthe human brain important for memory and cognition.

[0006] Smaller numbers of these lesions in a more restricted anatomicaldistribution are found in the brains of most aged humans who do not haveclinical AD. Amyloidogenic plaques and vascular amyloid angiopathy alsocharacterize the brains of individuals with Trisomy 21 (Down'sSyndrome), Hereditary Cerebral Hemorrhage with Amyloidosis of theDutch-Type (HCHWAD), and other neurodegenerative disorders. Beta-amyloidis a defining feature of AD, now believed to be a causative precursor orfactor in the development of disease. Deposition of A beta in areas ofthe brain responsible for cognitive activities is a major factor in thedevelopment of AD. Beta-amyloid plaques are predominantly composed ofamyloid beta peptide (A beta, also sometimes designated betaA4). A betapeptide is derived by proteolysis of the amyloid precursor protein (APP)and is comprised of 39-42 amino acids. Several proteases calledsecretases are involved in the processing of APP.

[0007] Cleavage of APP at the N-terminus of the A beta peptide bybeta-secretase and at the C-terminus by one or more gamma-secretasesconstitutes the beta-amyloidogenic pathway, i.e. the pathway by which Abeta is formed. Cleavage of APP by alpha-secretase produces alpha-sAPP,a secreted form of APP that does not result in beta-amyloid plaqueformation. This alternate pathway precludes the formation of A betapeptide. A description of the proteolytic processing fragments of APP isfound, for example, in U.S. Pat. Nos. 5,441,870; 5,721,130; and5,942,400.

[0008] An aspartyl protease has been identified as the enzymeresponsible for processing of APP at the beta-secretase cleavage site.The beta-secretase enzyme has been disclosed using varied nomenclature,including BACE, Asp, and Memapsin. See, for example, Sindha et al.,1999, Nature 402:537-554 (p501) and published PCT applicationWO00/17369.

[0009] Several lines of evidence indicate that progressive cerebraldeposition of beta-amyloid peptide (A beta) plays a seminal role in thepathogenesis of AD and can precede cognitive symptoms by years ordecades. See, for example, Selkoe, 1991, Neuron 6:487. Release of A betafrom neuronal cells grown in culture and the presence of A beta incerebrospinal fluid (CSF) of both normal individuals and AD patients hasbeen demonstrated. See, for example, Seubert et al., 1992, Nature359:325-327.

[0010] It has been proposed that A beta peptide accumulates as a resultof APP processing by beta-secretase, thus inhibition of this enzyme'sactivity is desirable for the treatment of AD. In vivo processing of APPat the beta-secretase cleavage site is thought to be a rate-limitingstep in A beta production, and is thus a therapeutic target for thetreatment of AD. See for example, Sabbagh, M., et al., 1997, Alz. Dis.Rev. 3, 1-19.

[0011] BACE1 knockout mice fail to produce A beta, and present a normalphenotype. When crossed with transgenic mice that over express APP, theprogeny show reduced amounts of A beta in brain extracts as comparedwith control animals (Luo et al., 2001 Nature Neuroscience 4:231-232).This evidence further supports the proposal that inhibition ofbeta-secretase activity and reduction of A beta in the brain provides atherapeutic method for the treatment of AD and other beta amyloiddisorders.

[0012] At present there are no effective treatments for halting,preventing, or reversing the progression of Alzheimer's disease.Therefore, there is an urgent need for pharmaceutical agents capable ofslowing the progression of Alzheimer's disease and/or preventing it inthe first place.

[0013] Compounds that are effective inhibitors of beta-secretase, thatinhibit beta-secretase-mediated cleavage of APP, that are effectiveinhibitors of A beta production, and/or are effective to reduce amyloidbeta deposits or plaques, are needed for the treatment and prevention ofdisease characterized by amyloid beta deposits or plaques, such as AD.Various pharmaceutical agents have been proposed for the treatment ofAlzheimer's disease but without any real success.

[0014] At present there are no effective treatments for halting,preventing, or reversing the progression of Alzheimer's disease. Thereis an urgent need for compounds capable of slowing A-beta peptideproduction and/or deposition in the brain, which presents a therapeuticapproach to treatment of Alzheimer's disease.

SUMMARY OF THE INVENTION

[0015] The invention provides compounds of the formula below,pharmaceutical compositions containing the compounds, and methods usefulin the treatment of Alzheimer's disease. More specifically, it providescompounds that are capable of inhibiting beta-secretase, an enzyme thatcleaves amyloid precursor protein to produce A beta peptide, a majorcomponent of the amyloid plaques found in the brains of Alzheimer'ssufferers.

[0016] Accordingly, in a broad aspect, the invention is provides towardscompounds of formula I:

[0017] and pharmaceutically acceptable salts or esters thereof, where Rcis

[0018] (I) —C₁-C₁₀ alkyl optionally substituted with one, two or threegroups independently selected from the group consisting of C₁-C₃ alkyl,halogen, —OH, —SH, —C≡N, —CF₃, C₁-C₆ alkoxy, —O-phenyl,—NR_(1-a)R_(1-b), —OC═O NR_(1-a)R_(1-b), —S(═O)₀₋₂ R_(1-a), —NR_(1-a)C═ONR_(1-a)R_(1-b), —C═O NR_(1-a)R_(1-b), and —S(═O)₂ NR_(1-a)R_(1-b)wherein

[0019] R_(1-a) and R_(1-b) at each occurrence are independently H orC₁-C₆ alkyl,

[0020] (II) —(CH₂)₀₋₃—(C₃-C₈) cycloalkyl where cycloalkyl can beoptionally substituted with one, two or three substituents independentlyselected from the group consisting of C₁-C₃ alkyl, halogen, —OH, —SH,—C≡N, —CF₃, C₁-C₆ alkoxy, —O-phenyl, —CO₂H, —CO₂-(C₁-C₄ alkyl), and—NR_(1-a)R_(1-b)

[0021] (III) —(CR_(C-x)R_(C-y))₀₋₄—R_(C-aryl) where R_(C-x) and R_(C-y)are independently selected from the group consisting of

[0022] —H,

[0023] C₁-C₄ alkyl optionally substituted with 1 or 2 —OH,

[0024] C₁-C₄ alkoxy optionally substituted with 1, 2, or 3 halogen,

[0025] —(CH₂)₀₋₄—C₃-C₈ cycloalkyl,

[0026] C₂-C₆ alkenyl containing one or two double bonds,

[0027] C₂-C₆ alkynyl containing one or two triple bonds, and phenyl,

[0028] or

[0029] R_(C-x) and R_(C-y) are taken together with the carbon to whichthey are attached to form a carbocycle of three, four, five, six orseven carbon atoms, where one carbon atom is optionally replaced by agroup selected from —O—, —S—, —SO₂—, —NR_(N-2)— and R_(C-aryl), wherein

[0030] R_(C-aryl) at each occurrence is independently phenyl; naphthyl;tetralinyl; indanyl; dihydronaphthyl; or6,7,8,9-tetrahydro-5H-benzo[a]cycloheptenyl, each of which is optionallysubstituted with 1, 2, or 3 groups that are independently:

[0031] (1) C₁-C₆ alkyl, optionally substituted with one, two or threesubstituents selected from the group consisting of C₁-C₃ alkyl, halogen,—OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b),

[0032] (2) —OH,

[0033] (3) —NO₂,

[0034] (4) halogen,

[0035] (5) —CO₂H,

[0036] (6) —C≡N,

[0037] (7) —(CH₂)₀₋₄—CO—NR_(N-2)R_(N-3) where

[0038] R_(N-2) and R_(N-3) are independently selected from the groupconsisting of:

[0039] (a) —H,

[0040] (b) —C₁-C₆ alkyl optionally substituted with one substituentselected from the group consisting of:

[0041] (i) —OH, and

[0042] (ii) —NH₂,

[0043] (c) —C₁-C₆ alkyl optionally substituted with 1, 2, or 3 groupsthat are independently —F, —Cl, —Br, —I, or OH,

[0044] (d) —C₃-C₇ cycloalkyl,

[0045] (e) —(C₁-C₂ alkyl)-(C₃-C₇ cycloalkyl),

[0046] (f) —(C₁-C₆ alkyl)-O-(C₁-C₃ alkyl)

[0047] (g) —C₂-C₆ alkenyl

[0048] (h) —C₂-C₆ alkynyl

[0049] (i) —C₁-C₆ alkyl chain with one double bond and one triple bond,

[0050] (j) —R_(1-aryl) wherein R_(1-aryl) at each occurrence isindependently phenyl, naphthyl, indanyl, indenyl, dihydronaphthyl, ortetralinyl each of which is optionally substituted with 1, 2, 3, or 4groups that are independently:

[0051] (i) C₁-C₆ alkyl optionally substituted with one, two or threesubstituents independently selected from the group consisting of C₁-C₃alkyl, —F, —Cl, —Br, —I, —OH, —SH, —NR_(1-a)R_(1-b), —C≡N, —CF₃, andC₁-C₃ alkoxy,

[0052] (ii) C₂-C₆ alkenyl with one or two double bonds, optionallysubstituted with one, two or three substituents independently selectedfrom the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃alkoxy, and —NR_(1-a)R_(1-b),

[0053] (iii) C₂-C₆ alkynyl optionally substituted with 1, 2, or 3 groupsthat are independently selected from the group consisting of —F, —Cl,—OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b),

[0054] (iv) —F, Cl, —Br and —I,

[0055] (v) —C₁-C₆ alkoxy optionally substituted with 1, 2, or 3 —F,

[0056] (vi) —NR_(N-2)R_(N-3),

[0057] (vii) —OH,

[0058] (viii) —C≡N,

[0059] (ix) C₃-C₇ cycloalkyl, optionally substituted with 1, 2, or 3groups that are selected from the group consisting of —F, —Cl, —OH, —SH,—C≡N, —CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b),

[0060] (x) —CO-(C₁-C₄ alkyl),

[0061] (xi) —SO₂—NR_(1-a)R_(1-b),

[0062] (xii) —CO—NR_(1-a)R_(1-b), or

[0063] (xiii) —SO₂-(C₁-C₄ alkyl)

[0064] (k) —R₁-heteroaryl wherein R₁-heteroaryl at each occurrence isindependently selected from the group consisting of pyridinyl,pyrimidinyl, quinolinyl, benzothienyl, indolyl, indolinyl, pryidazinyl,pyrazinyl, isoindolyl, isoquinolyl, quinazolinyl, quinoxalinyl,phthalazinyl, imidazolyl, isoxazolyl, pyrazolyl, oxazolyl, thiazolyl,indolizinyl, indazolyl, benzothiazolyl, benzimidazolyl, benzofuranyl,furanyl, thienyl, pyrrolyl, oxadiazolyl, thiadiazolyl, triazolyl,tetrazolyl, oxazolopyridinyl, imidazopyridinyl, isothiazolyl,naphthyridinyl, cinnolinyl, carbazolyl, beta-carbolinyl, isochromanyl,chromanyl, tetrahydroisoquinolinyl, isoindolinyl,isobenzotetrahydrofuranyl, isobenzotetrahydrothienyl, isobenzothienyl,benzoxazolyl, pyridopyridinyl, benzotetrahydrofuranyl,benzotetrahydrothienyl, purinyl, benzodioxolyl, triazinyl, phenoxazinyl,phenothiazinyl, pteridinyl, benzothiazolyl, imidazopyridinyl,imidazothiazolyl, dihydrobenzisoxazinyl, benzisoxazinyl, benzoxazinyl,dihydrobenzisothiazinyl, benzopyranyl, benzothiopyranyl, coumarinyl,isocoumarinyl, chromonyl, chromanonyl, pyridinyl-N-oxide,tetrahydroquinolinyl, dihydroquinolinyl, dihydroquinolinonyl,dihydroisoquinolinonyl, dihydrocoumarinyl, dihydroisocoumarinyl,isoindolinonyl, benzodioxanyl, benzoxazolinonyl, pyrrolyl N-oxide,pyrimidinyl N-oxide, pyridazinyl N-oxide, pyrazinyl N-oxide, quinolinylN-oxide, indolyl N-oxide, indolinyl N-oxide, isoquinolyl N-oxide,quinazolinyl N-oxide, quinoxalinyl N-oxide, phthalazinyl N-oxide,imidazolyl N-oxide, isoxazolyl N-oxide, oxazolyl N-oxide, thiazolylN-oxide, indolizinyl N-oxide, indazolyl N-oxide, benzothiazolyl N-oxide,benzimidazolyl N-oxide, pyrrolyl N-oxide, oxadiazolyl N-oxide,thiadiazolyl N-oxide, triazolyl N-oxide, tetrazolyl N-oxide,benzothiopyranyl S-oxide, and benzothiopyranyl S,S-dioxide,

[0065] where the R_(1-heteroaryl) group is optionally substituted with1, 2, 3, or 4 groups that are independently:

[0066] (i) C₁-C₆ alkyl optionally substituted with 1, 2, or 3 groupsindependently selected from the group consisting of C₁-C₃ alkyl, —F,—Cl, —Br, —I, —OH, —SH, —NR_(1-a)R_(1-b), —C≡N, —CF₃, and C₁-C₃ alkoxy,

[0067] (ii) C₂-C₆ alkenyl optionally substituted with 1, 2, or 3 groupsthat are independently —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and—NR_(1-a)R_(1-b),

[0068] (iii) C₂-C₆ alkynyl optionally substituted with 1, 2, or 3 groupsthat are independently selected from the group consisting of —F, —Cl,—OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b),

[0069] (iv) —F, —Cl, —Br and —I,

[0070] (v) —C₁-C₆ alkoxy optionally substituted with one, two, or three—F,

[0071] (vi) —(CH₂)₀₋₄ —NR_(N-2)R_(N-3),

[0072] (vii) —OH,

[0073] (viii) —C≡N,

[0074] (ix) (CH₂)₀₋₄—C₃-C₇ cycloalkyl, optionally substituted with 1, 2,or 3 groups that are independently selected from the group consisting of—F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b),

[0075] (x) (CH₂)₀₋₄—CO-(C₁-C₆ alkyl),

[0076] (xi) (CH₂)₀₋₄—SO₂—NR_(N-2)R_(N-3),

[0077] (xii) (CH₂)₀₋₄—CO—NR_(N-2)R_(N-3),

[0078] (xiii) (CH₂)₀₋₄—SO₂-(C₁-C₆ alkyl),

[0079] (xiv) (CH₂)₀₋₄—N(R_(N-2))—SO₂—, and

[0080] (xv) (CH₂)₀₋₄—N (R_(N-2))—C(O)—,

[0081] (8) —(CH₂)₀₋₄—CO-(C₁-C₁₂ alkyl),

[0082] (9) —(CH₂)₀₋₄—CO-(C₂-C₁₂ alkenyl),

[0083] (10) —(CH₂)₀₋₄—CO-(C₂-C₁₂ alkynyl),

[0084] (11) —(CH₂)₀₋₄—CO—(CH₂)₀₋₄ (C₃-C₇ cycloalkyl),

[0085] (12) —(CH₂)₀₋₄—CO—R_(1-aryl),

[0086] (13) —(CH₂)₀₋₄—CO—R_(1-heteroaryl),

[0087] (14) —(CH₂)₀₋₄—CO—R_(1-heterocycle) wherein

[0088] R_(1-heterocycle) at each occurrence is independently selectedfrom the group consisting of morpholinyl, thiomorpholinyl,thiomorpholinyl S-oxide, thiomorpholinyl S,S-dioxide, piperazinyl,homopiperazinyl, pyrrolidinyl, pyrrolinyl, tetrahydropyranyl,piperidinyl, tetrahydrofuranyl, tetrahydrothienyl, homopiperidinyl,homomorpholinyl, homothiomorpholinyl, homothiomorpholinyl S,S-dioxide,oxazolidinonyl, dihydropyrazolyl, dihydropyrrolyl, dihydropyrazinyl,dihydropyridinyl, dihydropyrimidinyl, dihydrofuryl, dihydropyranyl,tetrahydrothienyl S-oxide, tetrahydrothienyl S,S-dioxide, andhomothiomorpholinyl S-oxide,

[0089] where the R_(1-heterocycle) group is bonded by any atom of theparent R_(1-heterocycle) group substituted by hydrogen such that the newbond to the R_(1-heterocycle) group replaces the hydrogen atom and itsbond, where heterocycle is optionally substituted with 1, 2, 3, or 4groups that are independently:

[0090] (a) C₁-C₆ alkyl optionally substituted with one, two or threesubstituents independently selected from the group consisting of C₁-C₃alkyl, halogen, —OH, —SH, —NR_(1-a)R_(1-b) —C≡N, —CF₃, and C₁-C₃ alkoxy,

[0091] (b) C₂-C₆ alkenyl with one or two double bonds, optionallysubstituted with one, two or three substituents independently selectedfrom the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃alkoxy, and —NR_(1-a)R_(1-b)

[0092] (c) C₂-C₆ alkynyl with one or two triple bonds, optionallysubstituted with one, two or three substituents independently selectedfrom the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃alkoxy, and —NR_(1-a)R_(1-b)

[0093] (d) halogen,

[0094] (e) C₁-C₆ alkoxy,

[0095] (f) —C₁-C₆ alkoxy optionally substituted with one, two, or three—F,

[0096] (g) —NR_(N-2)R_(N-3),

[0097] (h) —OH,

[0098] (i) —C≡N,

[0099] (j ) (CH₂)₀₋₄-(C₃-C₇ cycloalkyl) optionally substituted with 1,2, or 3 groups independently selected from the group consisting of —F,—Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b),

[0100] (k) —(CH₂)₀₋₄—CO-(C₁-C₄ alkyl),

[0101] (l) —(CH₂)₀₋₄—SO₂—NR_(1-a)R_(1-b),

[0102] (m) —(CH₂)₀₋₄—CO—NR_(1-a)R_(1-b),

[0103] (n) —(CH₂)₀₋₄—SO₂-(C₁-C₆ alkyl), and

[0104] (o) ═O,

[0105] (p) —(CH₂)₀₋₄—N(R_(N-2))—SO₂—

[0106] (q) —(CH₂)₀₋₄—N(R_(N-2))—C(O)—

[0107] (15) —(CH₂)₀₋₄—CO—R_(N-4) wherein

[0108] R_(N-4) at each occurrence is independently selected from thegroup consisting of morpholinyl, thiomorpholinyl, pyrrolidinonyl,pyrrolyl, pyrazolyl, thienyl, pyridyl N-oxide, piperazinyl, piperidinyl,homomorpholinyl, homothiomorpholinyl, homothiomorpholinyl S-oxide,homothiomorpholinyl S,S-dioxide, pyrrolinyl and pyrrolidinyl where eachgroup is optionally substituted with 1, 2, 3, or 4 groups that areindependently C₁-C₆ alkyl,

[0109] (16) —(CH₂)0-4—CO₂—R_(N-5) where

[0110] R_(N-5) at each occurrence is independently selected from thegroup consisting of:

[0111] (a) C₁-C₆ alkyl,

[0112] (b) —(CH₂)₀₋₂—(R_(1-aryl)),

[0113] (c) C₂-C₆ alkenyl,

[0114] (d) C₂-C₆ alkynyl,

[0115] (e) C₃-C₇ cycloalkyl, and

[0116] (f) —(CH₂)₀₋₄—(R_(1-heteroaryl)),

[0117] (17) —(CH₂)₀₋₄—SO₂—NR_(N-2)R_(N-3)

[0118] (18) —(CH₂)₀₋₄—SO-(C₁-C₈ alkyl),

[0119] (19) —(CH₂)₀₋₄—SO₂-(C₁-C₁₂ alkyl),

[0120] (20) —(CH₂)₀₋₄—SO₂-(C₃-C₇ cycloalkyl)

[0121] (21) —(CH₂)₀₋₄—N(H or R_(N-5))—CO₂—R_(N-5),

[0122] (22) —(CH₂)₀₋₄—N(H or R_(N-5))—CO—N(R_(N-5))₂,

[0123] (23) —(CH₂)₀₋₄—N—CS—N(R_(N-5))₂,

[0124] (24) —(CH₂)₀₋₄—N(—H or R_(N-5))—CO—R_(N-2),

[0125] (25) —(CH₂)₀₋₄—NR_(N-2)R_(N-3),

[0126] (26) —(CH₂)₀₋₄—R_(N-4),

[0127] (27) —(CH₂)₀₋₄—O—CO-(C₁-C₆ alkyl)

[0128] (28) —(CH₂)₀₋₄—O—P(O)—(OR₁₀₀)₂ where R₁₀₀ is independently H orC₁-C₄ alkyl,

[0129] (29) —(CH₂)₀₋₄—O—CO—N(R_(N-5))₂,

[0130] (30) —(CH₂)₀₋₄—O—CS—N(R_(N-5))₂,

[0131] (31) —(CH₂)₀₋₄—O—(R_(N-5)),

[0132] (32) —(CH₂)₀₋₄—O—(R_(N-5))—COOH,

[0133] (33) —(CH₂)₀₋₄—S—(R_(N-5)),

[0134] (34) —(CH₂)₀₋₄—O-(C₁-C₆ alkyl) wherein the alkyl group isoptionally substituted with one, two, three, four, or five substituentsindependently selected from the group consisting of F, Cl, Br, and I,

[0135] (35) —(CH₂)₀₋₄-(C₃-C₈ cycloalkyl),

[0136] (36) C₂-C₆ alkenyl optionally substituted with C₁-C₃ alkyl,halogen, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, or —NR_(1-a)R_(1-b),

[0137] (37) C₂-C₆ alkynyl optionally substituted with C₁-C₃ alkyl, —F,—Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, or —NR_(1-a)R_(1-b),and

[0138] (38) —(CH₂)₀₋₄—N(—H or R_(N-5))—SO₂—R_(N-2);

[0139] (IV) —(CR_(C-x)R_(C-y))₀₋₄-R_(C-heteroaryl) wherein

[0140] R_(C-heteroaryl) at each occurrence is independently selectedfrom the group consisting of pyridinyl, pyrimidinyl, quinolinyl,benzothienyl, indolyl, indolinyl, pryidazinyl, pyrazinyl, isoindolyl,isoquinolyl, quinazolinyl, quinoxalinyl, phthalazinyl, imidazolyl,isoxazolyl, pyrazolyl, oxazolyl, thiazolyl, indolizinyl, indazolyl,benzoisothiazolyl, benzimidazolyl, benzofuranyl, furanyl, thienyl,pyrrolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl,oxazolopyridinyl, isothiazolyl, naphthyridinyl, cinnolinyl, carbazolyl,beta-carbolinyl, isochromanyl, chromanyl, tetrahydroisoquinolinyl,isoindolinyl, isobenzotetrahydrofuranyl, isobenzotetrahydrothienyl,isobenzothienyl, benzoxazolyl, pyridopyridinyl, benzotetrahydrofuranyl,benzotetrahydrothienyl, purinyl, benzodioxolyl, triazinyl, henoxazinyl,phenothiazinyl, pteridinyl, benzothiazolyl, imidazopyridinyl,imidazothiazolyl, dihydrobenzisoxazinyl, benzisoxazinyl, benzoxazinyl,dihydrobenzisothiazinyl, benzopyranyl, benzothiopyranyl, coumarinyl,isocoumarinyl, chromonyl, chromanonyl, tetrahydroquinolinyl,dihydroquinolinyl, dihydroquinolinonyl, dihydroisoquinolinonyl,dihydrocoumarinyl, dihydroisocoumarinyl, isoindolinonyl, benzodioxanyl,benzoxazolinonyl, imidazopyrazolyl, quinazolinonyl, pyrazopyridyl,benzooxadiazolyl, dihydropyrimidinonyl, dihydrobenzofuranonyl,pyridinyl-N-oxide, pyrrolyl N-oxide, pyrimidinyl N-oxide, pyridazinylN-oxide, pyrazinyl N-oxide, quinolinyl N-oxide, indolyl N-oxide,indolinyl N-oxide, isoquinolyl N-oxide, quinazolinyl N-oxide,quinoxalinyl N-oxide, phthalazinyl N-oxide, imidazolyl N-oxide,isoxazolyl N-oxide, oxazolyl N-oxide, thiazolyl N-oxide, indolizinylN-oxide, indazolyl N-oxide, benzothiazolyl N-oxide, benzimidazolylN-oxide, pyrrolyl N-oxide, oxadiazolyl N-oxide, thiadiazolyl N-oxide,triazolyl N-oxide, tetrazolyl N-oxide, benzothiopyranyl S-oxide, andbenzothiopyranyl S,S-dioxide,

[0141] where the R_(C-heteroaryl) group is bonded by any atom of theparent RC heteroaryl group substituted by hydrogen such that the newbond to the RC-heteroaryl group replaces the hydrogen atom and its bond,where heteroaryl is optionally substituted 1, 2, 3, or 4 groups that areindependently:

[0142] (1) C₁-C₆ alkyl, optionally substituted with 1, 2, or 3 groupsindependently selected from the group consisting of C₁-C₃ alkyl, —F,—Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b),

[0143] (2) —OH,

[0144] (3) —NO₂,

[0145] (4) —F, —Cl, —Br, —I,

[0146] (5) —CO—OH,

[0147] (6) —C≡N,

[0148] (7) —(CH₂)₀₋₄—CO—NR_(N-2)R_(N-3),

[0149] (8) —(CH₂)₀₋₄—CO-(C₁-C₁₂ alkyl),

[0150] (9) —(CH₂)₀₋₄—CO-(C₂-C₁₂ alkenyl with one, two or three doublebonds),

[0151] (10) —(CH₂)₀₋₄—CO-(C₂-C₁₂ alkynyl with one, two or three triplebonds),

[0152] (11) —(CH₂)₀₋₄—CO-(C₃-C₇ cycloalkyl),

[0153] (12) —(CH₂)₀₋₄—CO—R_(1-aryl) where R_(1-aryl) is as definedabove,

[0154] (13) —(CH₂)₀₋₄—CO—R_(1 -heteroaryl),

[0155] (14) —(CH₂)₀₋₄—CO—R_(1-heterocycle),

[0156] (15) —(CH₂)₀₋₄—CO—R_(N-4),

[0157] (16) —(CH₂)₀₋₄—CO—O—R_(N-5),

[0158] (17) —(CH₂)₀₋₄—SO₂—NR_(N-2)R_(N-3),

[0159] (18) —(CH₂)₀₋₄—SO-(C₁-C₈ alkyl),

[0160] (19) —(CH₂)₀₋₄—SO₂-(C₁-C₁₂ alkyl),

[0161] (20) —(CH₂)₀₋₄—SO₂-(C₃-C₇ cycloalkyl),

[0162] (21) —(CH₂)₀₋₄—N(H or R_(N-5))—CO—O—R_(N-5),

[0163] (22) —(CH₂)₀₋₄—N(H or R_(N-5))—CO—N(R_(N-5))₂,

[0164] (23) —(CH₂)₀₋₄—N—CS—N(R_(N-5))₂,

[0165] (24) —(CH₂)₀₋₄—N(—H or R_(N-5))—CO—R_(N-2),

[0166] (25) —(CH₂)₀₋₄—NR_(N-2)R_(N-3),

[0167] (26) —(CH₂)₀₋₄—R_(N-4),

[0168] (27) —(CH₂)₀₋₄—O—CO-(C₁-C₆ alkyl)

[0169] (28) —(CH₂)₀₋₄—O—P(O)—(OR₁₀₀)₂ where R₁₀₀ is —H or C₁-C₄ alkyl,

[0170] (29) —(CH₂)₀₋₄—O—CO—N(R_(N-5))₂,

[0171] (30) —(CH₂)₀₋₄—O—CS—N(R_(N-5))₂,

[0172] (31) —(CH₂)₀₋₄—O—(R_(N-5)),

[0173] (32) —(CH₂)₀₋₄—O—(R_(N-5))—COOH,

[0174] (33) —(CH₂)₀₋₄—S—(R_(N-5)),

[0175] (34) —(CH₂)₀₋₄—O-(C₁-C₆ alkyl optionally substituted with one,two, three, four, or five of —F),

[0176] (35) C₃-C₇ cycloalkyl,

[0177] (36) C₂-C₆ alkenyl optionally substituted with C₁-C₃ alkyl, —F,—Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, or —NR_(1-a)R_(1-b),

[0178] (37) C₂-C₆ alkynyl optionally substituted with C₁-C₃ alkyl, —F,—Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, or —NR_(1-a)R_(1-b),

[0179] (38) —(CH₂)₀₋₄—N(—H or R_(N-5))—SO₂—R_(N-2),

[0180] (39) —(CH₂)₀₋₄-(C₃-C₇ cycloalkyl)

[0181] (V) —(CR_(C-x)R_(C-y))₀₋₄—R_(C-aryl)—R₁₀₁—R_(C-aryl),

[0182] (VI) —(CR_(C-x)R_(C-y))₀₋₄—R_(C-aryl)—R₁₀₁—R_(C-heteroaryl),

[0183] (VII) —(CR_(C-x)R_(C-y))₀₋₄—R_(C-heteroaryl)—R₁₀₁—R_(C-aryl),

[0184] (VIII)—(CR_(C-x)R_(C-y))₀₋₄—R_(C-heteroaryl)—R₁₀₁—R_(C-heteroaryl),

[0185] (IX) —(CR_(C-x)R_(C-y))₀₋₄—R_(C-aryl)—R₁₀₁—R_(1-heterocycle),

[0186] (X)—(CR_(C-x)R_(C-y))₀₋₄—R_(C-heteroaryl)—R₁₀₁—R_(1-heterocycle),

[0187] (XI) —(CR_(C-x)R_(C-y))₀₋₄—R_(1-heterocycle)—R₁₀₁—R_(C-aryl),

[0188] (XII) —(CR_(C-x)R_(C-y))₀₋₄—R_(1-heterocycle)—R₁₀₁—R_(C-heteroaryl),

[0189] (XIII)—(CR_(C-x)R_(C-y))₀₋₄—R_(1-heterocycle)—R₁₀₁—R_(1-heterocycle), whereinR₁₀₁ is a bond, (CH₂)₀₋₄, —O—, —NH—, or —N(C₁-C₆ alkyl)

[0190] (XIV) —(CR_(C-x)R_(C-y))₀₋₄—R_(1-heterocycle),

[0191] (XV) —[C(R_(C-1))(R_(C-2))]₁₋₃—CO—N(R_(C-3))₂ where R_(C-1) andR_(C-2) are the same or different and are selected from the groupconsisting of:

[0192] (A) —H,

[0193] (B) —C₁-C₆ alkyl, optionally substituted with one, two or threesubstituents independently selected from the group consisting of C₁-C₃alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁-C₆ alkoxy, —O-phenyl,and —NR_(1-a)R_(1-b),

[0194] (C) C₂-C₆ alkenyl with one or two double bonds, optionallysubstituted with one, two or three substituents independently selectedfrom the group consisting of C₁-C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH,—C≡N, —CF₃, C₁-C6 alkoxy, —O-phenyl, and —NR_(1-a)R_(1-b),

[0195] (D) C₂-C₆ alkynyl optionally substituted with one, two or threesubstituents independently selected from the group consisting of C₁-C₃alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁-C₆ alkoxy, —O-phenyl,and —NR_(1-a)R_(1-b),

[0196] (E) —(CH₂)₁₋₂—S(O)₀₋₂-(C₁-C₆ alkyl),

[0197] (F) —(CH₂)₀₋₄—C₃-C₇ cycloalkyl, optionally substituted with one,two or three substituents independently selected from the groupconsisting of C₁-C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁-C₆alkoxy, —O-phenyl, and —NR_(1-a)R_(1-b),

[0198] (G) —(C₁-C₄ alkyl)-R_(1-aryl),

[0199] (H) —(C₁-C₄ alkyl)-R_(C-heteroaryl),

[0200] (I) —(C₁-C₄ alkyl)-R_(1-heterocycle),

[0201] (J) —R_(C-heteroaryl),

[0202] (K) —R_(1-heterocycle),

[0203] (M) —(CH₂)₁₋₄—R_(C-4)—(CH₂)₀₋₄—R_(1-aryl) where R_(C-4) is —O—,—S— or —NR(C₁-C₆ alkyl)-,

[0204] (N) —(CH₂)₁₋₄—R_(C-4)—(CH₂)₀₋₄—R_(C-heteroaryl),

[0205] (O) —R_(1-aryl),

[0206] and where

[0207] R_(C-3) at each occurrence is independently:

[0208] (A) —H,

[0209] (B) —C₁-C₆ alkyl optionally substituted with one, two or threesubstituents independently selected from the group consisting of C₁-C₃alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁-C₆ alkoxy, —O-phenyl,and —NR_(1-a)R_(1-b),

[0210] (C) C₂-C₆ alkenyl with one or two double bonds, optionallysubstituted with one, two or three substituents independently selectedfrom the group consisting of C₁-C₃ alkyl, halogen, —OH, —SH, —C≡N, —CF₃,C₁-C₆ alkoxy, —O-phenyl, and —NR_(1-a)R_(1-b),

[0211] (D) C₂-C₆ alkynyl with one or two triple bonds, optionallysubstituted with one, two or three substituents independently selectedfrom the group consisting of C₁-C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH,—C≡N, —CF₃, C₁-C₆ alkoxy, —O-phenyl, and —NR_(1-a)R_(1-b),

[0212] (E) —(CH₂)₀₋₄—C₃-C₇ cycloalkyl, optionally substituted with 1, 2,or 3 groups that are independently selected from the group consisting ofC₁-C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁-C₆ alkoxy,—O-phenyl, and —NR_(1-a)R_(1-b),

[0213] (F) —R_(1-aryl),

[0214] (G) —R_(C-heteroaryl),

[0215] (H) —R_(1-heterocycle),

[0216] (I) —(C₁-C₄ alkyl)-R_(1-aryl),

[0217] (J) —(C₁-C₄ alkyl)-R_(C-heteroaryl),

[0218] (K) —(C₁-C₄ alkyl)-R_(1-heterocycle),

[0219] (XVI) —CH(R_(C-aryl))₂,

[0220] (XVII) —CH(R_(C-heteroaryl))₂,

[0221] (XVIII) —CH(R_(C-aryl))(R_(C-heteroaryl)),

[0222] (XIX) -cyclopentyl, -cyclohexyl, or -cycloheptyl ring fused toR_(C-aryl) or R_(C-heteroaryl) or R_(1-heterocycle) where R_(C-aryl) orR_(C-heteroaryl) or R_(1-heterocycle) are as defined above where onecarbon of cyclopentyl, cyclohexyl, or -cycloheptyl is optionallyreplaced with NH, NR_(N-5), O, S(═O)₀₋₂, and where cyclopentyl,cyclohexyl, or -cycloheptyl can be optionally substituted with one ortwo —C₁-C₃ alkyl, —F, —OH, —SH, —C≡N, —CF₃, C₁-C₆ alkoxy, ═O, or—NR_(1-a)R_(1-b),

[0223] (XX) C₂-C₁₀ alkenyl optionally substituted with one, two or threesubstituents independently selected from the group consisting of C₁-C₃alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁-C₆ alkoxy, —O-phenyl,and —NR_(1-a)R_(1-b),

[0224] (XXI) C₂-C₁₀ alkynyl optionally substituted with one, two orthree substituents independently selected from the group consisting ofC₁-C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁-C₆ alkoxy,—O-phenyl, and —NR_(1-a)R_(1-b),

[0225] (XXI) —(CH₂)₀₋₁—CHR_(C-6)—(CH₂)₀₋₁—R_(C-aryl) wherein R_(C-6) is—(CH₂)₀₋₆—OH,

[0226] (XXII) —(CH₂)₀₋₁—CHR_(C-6)—(CH₂)₀₋₁—R_(C-heteroaryl),

[0227] (XXIII) —CH(—R_(C-aryl) or R_(C-heteroaryl))—CO—O(C₁-C₄ alkyl)

[0228] (XXIV) —CH(—CH₂—OH)—CH(—OH)-alkyl-NO₂,

[0229] (XXV) —(C₁-C₆ alkyl)-O-(C₁-C₆ alkyl)-OH,

[0230] (XXVII) —CH₂—NH—CH₂—CH(—O—CH₂—CH₃)₂,

[0231] (XXVIII) —H, and

[0232] (XXIX) —(CH₂)₀₋₆—C(═NR_(1-a))(NR_(1-a)R_(1-b));

[0233] where R_(N) is

[0234] (I) R_(N-1)—X_(N)— where X_(N) is selected from the groupconsisting of:

[0235] (A) —CO—,

[0236] (B) —SO₂—,

[0237] (C) —(CR′″R′″)₁₋₆ wherein

[0238] R′″ and R′″ at each occurrence are the same or different and are—H or C₁-C₄ alkyl,

[0239] (D) —CO—(CR″R′″)₁₋₆—X_(N-1) wherein

[0240] X_(N-1) is selected from the group consisting of —O—, —S— and—NR″—,

[0241] (E) a single bond, and

[0242] (F) —CO—(CR″R′″)₁₋₆—

[0243] where R_(N-1) is selected from the group consisting of:

[0244] (A) R_(N-aryl) wherein R_(N-aryl) at each occurrence isindependently phenyl; naphthyl; tetralinyl; indanyl; indenyl;dihydronaphthyl; or 6,7,8,9-tetrahydro-5H-benzo[a]cycloheptenyl; each ofwhich is optionally substituted with one, two or three of the followingsubstituents which can be the same or different and are:

[0245] (1) C₁-C₆ alkyl, optionally substituted with one, two or threesubstituents selected from the group consisting of C₁-C₃ alkyl, —F, —Cl,—Br, —I, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b),

[0246] wherein R_(1-a) and R_(1-b) at each occurrence are independentlyH or C₁-C₆ alkyl,

[0247] (2) —OH,

[0248] (3) —NO₂,

[0249] (4) —F, —Cl, —Br, —I,

[0250] (5) —CO₂H,

[0251] (6) —C≡N,

[0252] (7) —(CH₂)₀₋₄—CO—NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) arethe same or different and are selected from the group consisting of:

[0253] (a) —H,

[0254] (b) —C₁-C₈ alkyl optionally substituted with one substituentselected from the group consisting of:

[0255] (i) —OH,

[0256] (ii) —NH₂,

[0257] (iii) phenyl,

[0258] (c) —C₁-C₈ alkyl optionally substituted with 1, 2, or 3 groupsthat are independently —F, —Cl, —Br, or —I,

[0259] (d) —C₃-C₈ cycloalkyl,

[0260] (e) —(C₁-C₂ alkyl)-(C₃-C₈ cycloalkyl),

[0261] (f) —(C₁-C₆ alkyl)-O-(C₁-C₃ alkyl),

[0262] (g) —C₂-C₆ alkenyl,

[0263] (h) —C₂-C₆ alkynyl,

[0264] (i) —C₁-C₆ alkyl chain with one double bond and one triple bond,

[0265] (j) —R_(1-aryl), wherein R_(1-aryl), at each occurrence isindependently phenyl, naphthyl, indanyl, indenyl, dihydronaphthyl, ortetralinyl each of which is optionally substituted with 1, 2, 3, or 4groups that are independently:

[0266] (i) C₁-C₆ alkyl optionally substituted with one, two or threesubstituents independently selected from the group consisting of C₁-C₃alkyl, —F, —Cl, —Br, —I, —OH, —SH, —NR_(1-a)R_(1-b), —C≡N, —CF₃, andC₁-C₃ alkoxy,

[0267] (ii) C₂-C₆ alkenyl with one or two double bonds, optionallysubstituted with one, two or three substituents independently selectedfrom the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃alkoxy, and —NR_(1-a)R_(1-b),

[0268] (iii) C₂-C₆ alkynyl optionally substituted with 1, 2, or 3 groupsthat are independently selected from the group consisting of —F, —Cl,—OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b),

[0269] (iv) —F, Cl, —Br and —I,

[0270] (v) —C₁-C₆ alkoxy optionally substituted with 1, 2, or 3 —F,

[0271] (vi) —NR_(N-2)R_(N-3),

[0272] (vii) —OH,

[0273] (viii) —C≡N,

[0274] (ix) C₃-C₇ cycloalkyl, optionally substituted with 1, 2, or 3groups that are selected from the group consisting of —F, —Cl, —OH, —SH,—C≡N, —CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b),

[0275] (x) —CO-(C₁-C₄ alkyl),

[0276] (xi) —SO₂—NR_(1-a)R_(1-b),

[0277] (xii) —CO—NR_(1-a)R_(1-b), or

[0278] (xiii) —SO₂-(C₁-C₄ alkyl)

[0279] (k) —R_(1-heteroaryl), wherein R_(1-heteroaryl) at eachoccurrence is independently selected from the group consisting ofpyridinyl, pyrimidinyl, quinolinyl, benzothienyl, indolyl, indolinyl,pryidazinyl, pyrazinyl, isoindolyl, isoquinolyl, quinazolinyl,quinoxalinyl, phthalazinyl, imidazolyl, isoxazolyl, pyrazolyl, oxazolyl,thiazolyl, indolizinyl, indazolyl, benzothiazolyl, benzimidazolyl,benzofuranyl, furanyl, thienyl, pyrrolyl, oxadiazolyl, thiadiazolyl,triazolyl, tetrazolyl, oxazolopyridinyl, imidazopyridinyl, isothiazolyl,naphthyridinyl, cinnolinyl, carbazolyl, beta-carbolinyl, isochromanyl,chromanyl, tetrahydroisoquinolinyl, isoindolinyl,isobenzotetrahydrofuranyl, isobenzotetrahydrothienyl, isobenzothienyl,benzoxazolyl, pyridopyridinyl, benzotetrahydrofuranyl,benzotetrahydrothienyl, purinyl, benzodioxolyl, triazinyl, phenoxazinyl,phenothiazinyl, pteridinyl, benzothiazolyl, imidazopyridinyl,imidazothiazolyl, dihydrobenzisoxazinyl, benzisoxazinyl, benzoxazinyl,dihydrobenzisothiazinyl, benzopyranyl, benzothiopyranyl, coumarinyl,isocoumarinyl, chromonyl, chromanonyl, pyridinyl-N-oxide,tetrahydroquinolinyl, dihydroquinolinyl, dihydroquinolinonyl,dihydroisoquinolinonyl, dihydrocoumarinyl, dihydroisocoumarinyl,isoindolinonyl, benzodioxanyl, benzoxazolinonyl, pyrrolyl N-oxide,pyrimidinyl N-oxide, pyridazinyl N-oxide, pyrazinyl N-oxide, quinolinylN-oxide, indolyl N-oxide, indolinyl N-oxide, isoquinolyl N-oxide,quinazolinyl N-oxide, quinoxalinyl N-oxide, phthalazinyl N-oxide,imidazolyl N-oxide, isoxazolyl N-oxide, oxazolyl N-oxide, thiazolylN-oxide, indolizinyl N-oxide, indazolyl N-oxide, benzothiazolyl N-oxide,benzimidazolyl N-oxide, pyrrolyl N-oxide, oxadiazolyl N-oxide,thiadiazolyl N-oxide, triazolyl N-oxide, tetrazolyl N-oxide,benzothiopyranyl S-oxide, and benzothiopyranyl S,S-dioxide,

[0280] where the R_(1-heteroaryl) group is optionally substituted with1, 2, 3, or 4 groups that are independently:

[0281] (i) C₁-C₆ alkyl optionally substituted with 1, 2, or 3 groupsindependently selected from the group consisting of C₁-C₃ alkyl, —F,—Cl, —Br, —I, —OH, —SH, —NR_(1-a)R_(1-b), —C≡N, —CF₃, and C₁-C₃ alkoxy,

[0282] (ii) C₂-C₆ alkenyl optionally substituted with 1, 2, or 3 groupsthat are independently —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, or—NR_(1-a)R_(1-b),

[0283] (iii) C₂-C₆ alkynyl optionally substituted with 1, 2, or 3 groupsthat are independently —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, or—NR_(1-a)R_(1-b),

[0284] (iv) —F, —Cl, —Br and —I,

[0285] (v) —C₁-C₆ alkoxy optionally substituted with one, two, or three—F,

[0286] (vi) —(CH₂ )₀₋₄—NR_(N-2)R_(N-3),

[0287] (vii) —OH,

[0288] (viii) —C≡N,

[0289] (ix) (CH₂)₀₋₄—C₃-C₇ cycloalkyl, optionally substituted with 1, 2,or 3 groups that are independently selected from the group consisting of—F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b),

[0290] (x) (CH₂)₀₋₄—CO—(C₁-C₆ alkyl),

[0291] (xi) (CH₂)₀₋₄—SO₂—NR_(N-2)R_(N-3),

[0292] (xii) (CH₂)₀₋₄—CO—NR_(N-2)R_(N-3),

[0293] (xiii) (CH₂)₀₋₄—SO₂-(C₁-C₆ alkyl),

[0294] (xiv) (CH₂)₀₋₄—N(R_(N-2))—SO₂—, and

[0295] (xv) (CH₂)₀₋₄—N(R_(N-2))—C(O)—,

[0296] (1) —R_(1-heterocyle), wherein

[0297] R_(1-heterocycle) at each occurrence is independently selectedfrom the group consisting of morpholinyl, thiomorpholinyl,thiomorpholinyl S-oxide, thiomorpholinyl S,S-dioxide, piperazinyl,homopiperazinyl, pyrrolidinyl, pyrrolinyl, tetrahydropyranyl,piperidinyl, tetrahydrofuranyl, tetrahydrothienyl, homopiperidinyl,homomorpholinyl, homothiomorpholinyl, homothiomorpholinyl S,S-dioxide,oxazolidinonyl, dihydropyrazolyl, dihydropyrrolyl, dihydropyrazinyl,dihydropyridinyl, dihydropyrimidinyl, dihydrofuryl, dihydropyranyl,tetrahydrothienyl S-oxide, tetrahydrothienyl S,S-dioxide, andhomothiomorpholinyl S-oxide,

[0298] where the R_(1-heterocycle) group is bonded by any atom of theparent R_(1-heterocycle) group substituted by hydrogen such that the newbond to the R_(1-heterocycle) group replaces the hydrogen atom and itsbond, where heterocycle is optionally substituted with 1, 2, 3, or 4groups that are independently:

[0299] (a) C₁-C₆ alkyl optionally substituted with one, two or threesubstituents independently selected from the group consisting of C₁-C₃alkyl, halogen, —OH, —SH, —NR_(1-a)R_(1-b) —C≡N, —CF₃, and C₁-C₃ alkoxy,

[0300] (b) C₂-C₆ alkenyl with one or two double bonds, optionallysubstituted with one, two or three substituents independently selectedfrom the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃alkoxy, and —NR_(1-a)R_(1-b)

[0301] (c) C₂-C₆ alkynyl with one or two triple bonds, optionallysubstituted with one, two or three substituents independently selectedfrom the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃alkoxy, and —NR_(1-a)R_(1-b)

[0302] (d) halogen,

[0303] (e) C₁-C₆ alkoxy,

[0304] (f) —C₁-C₆ alkoxy optionally substituted with one, two, or three—F,

[0305] (g) —NR_(N-2)R_(N-3),

[0306] (h) —OH,

[0307] (i) —C≡N,

[0308] (j) (CH₂)₀₋₄—(C₃-C₈ cycloalkyl), optionally substituted with 1,2, or 3 groups independently selected from the group consisting of —F,—Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b),

[0309] (k) —(CH₂)₀₋₄—CO-(C₁-C₄ alkyl),

[0310] (l) —(CH₂)₀₋₄—SO₂—NR_(1-a)R_(1-b),

[0311] (m) —(CH₂)₀₋₄—CO—NR_(1-a)R_(1-b),

[0312] (n) —(CH₂)₀₋₄—SO₂-(C₁-C₆ alkyl), and

[0313] (o) ═O,

[0314] (p) —(CH₂)₀₋₄—N(R_(N-2))—SO₂—

[0315] (q) —(CH₂)₀₋₄ —N(R_(N-2))—C(O)—

[0316] (8) —(CH₂)₀₋₄—CO-(C₁-C₁₂ alkyl),

[0317] (9) —(CH₂)₀₋₄—CO-(C₂-C₁₂ alkenyl)

[0318] (10) —(CH₂)₀₋₄—CO-(C₂-C₁₂ alkynyl)

[0319] (11) —(CH₂)₀₋₄—CO-(C₃-C₈ cycloalkyl),

[0320] (12) —(CH₂)₀₋₄—CO—R_(1-aryl),

[0321] (13) —(CH₂)₀₋₄—CO—R_(1-heteroaryl),

[0322] (14) —(CH₂)₀₋₄—CO—R_(1-heterocycle),

[0323] (15) —(CH₂)₀₋₄—CO—R_(N-4) wherein R_(N-4) is selected from thegroup consisting of phenyl, morpholinyl, thiomorpholinyl, piperazinyl,piperidinyl, homomorpholinyl, homothiomorpholinyl, homothiomorpholinylS-oxide, homothiomorpholinyl S,S-dioxide, pyrrolinyl, thienyl,pyrazolyl, pyridyl N-oxide, oxazolyl, thiazolyl, imidazolyl, andpyrrolidinyl where each group is optionally substituted with one, two,three, or four groups that are independently C₁-C₆ alkyl,

[0324] (16) —(CH₂)₀₋₄—CO—O—R_(N-5) where R_(N-5) is selected from thegroup consisting of:

[0325] (a) C₁-C₆ alkyl,

[0326] (b) —(CH₂)₀₋₂—(R_(1-aryl)),

[0327] (c) C₂-C₆ alkenyl,

[0328] (d) C₂-C₆ alkynyl,

[0329] (e) —(CH₂)₀₋₂—C₃-C₈ cycloalkyl,

[0330] (f) —(CH₂)₀₋₂—(R_(1-heteroaryl)), and

[0331] (g) —(CH₂)₀₋₂—(R_(1-heterocycle)),

[0332] (17) —(CH₂)₀₋₄—SO₂—NR_(N-2)R_(N-3),

[0333] (18) —(CH₂)₀₋₄—SO-(C₁-C₈ alkyl),

[0334] (19) —(CH₂)₀₋₄—SO₂-(C₁-C₁₂ alkyl),

[0335] (20) —(CH₂)₀₋₄—SO₂-(C₃-C₈ cycloalkyl),

[0336] (21) —(CH₂)₀₋₄—N(H or R_(N-5))—CO—O—R_(N-5),

[0337] (22) —(CH₂)₀₋₄—N(H or R_(N-5))—CO—N(R_(N-5))₂,

[0338] (23) —(CH₂)₀₋₄—N—CS—N(R_(N-5))₂,

[0339] (24) —(CH₂)₀₋₄—N(H or R_(N-5))—CO—R_(N-2),

[0340] (25) —(CH₂)₀₋₄—NR_(N-2)R_(N-3),

[0341] (26) —(CH₂)₀₋₄—R_(N-4),

[0342] (27) —(CH₂)₀₋₄—O—CO-(C₁-C₆ alkyl),

[0343] (28) —(CH₂)₀₋₄—O—P(O)—(OR₁₀₀)₂ wherein

[0344] R₁₀₀ at each occurrence is independently —H or C₁-C₄ alkyl,

[0345] (29) —(CH₂)₀₋₄—O—CO—N(R_(N-5))₂,

[0346] (30) —(CH₂)₀₋₄—O—CS—N(R_(N-5))₂,

[0347] (31) —(CH₂)₀₋₄—O—(R_(N-5)),

[0348] (32) —(CH₂)₀₋₄—O—(R_(N-5))—COOH,

[0349] (33) —(CH₂)₀₋₄—S—(R_(N-5)),

[0350] (34) —(CH₂)₀₋₄—O—(C₁-C₆ alkyl optionally substituted with one,two, three, four, or five of —F),

[0351] (35) C₃-C₈ cycloalkyl,

[0352] (36) C₂-C₆ alkenyl optionally substituted with C₁-C₃ alkyl, —F,—Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, or —NR_(1-a)R_(1-b),

[0353] (37) C₂-C₆ alkynyl optionally substituted with C₁-C₃ alkyl, —F,—Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, or —NR_(1-a)R_(1-b),

[0354] (38) —(CH₂)₀₋₄—N(H or R_(N-5))—SO₂—R_(N-2),

[0355] (39) —(CH₂)₁₋₄—(C₃-C₈ cycloalkyl),

[0356] (B) —R_(N-heteroaryl) where R_(N-heteroaryl) is selected from thegroup consisting of: pyridinyl, pyrimidinyl, quinolinyl, benzothienyl,indolyl, indolinyl, pryidazinyl, pyrazinyl, isoindolyl, isoquinolyl,quinazolinyl, quinoxalinyl, phthalazinyl, imidazolyl, isoxazolyl,pyrazolyl, oxazolyl, thiazolyl, indolizinyl, indazolyl,benzisothiazolyl, benzimidazolyl, benzofuranyl, furanyl, thienyl,pyrrolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl,oxazolopyridinyl, imidazopyridinyl, isothiazolyl, naphthyridinyl,cinnolinyl, carbazolyl, beta-carbolinyl, isochromanyl, chromanyl,tetrahydroisoquinolinyl, isoindolinyl, isobenzotetrahydrofuranyl,isobenzotetrahydrothienyl, isobenzothienyl, benzoxazolyl,pyridopyridinyl, benzotetrahydrofuranyl, benzotetrahydrothienyl,purinyl, benzodioxolyl, triazinyl, henoxazinyl, phenothiazinyl,pteridinyl, benzothiazolyl, imidazothiazolyl, dihydrobenzisoxazinyl,benzisoxazinyl, benzoxazinyl, dihydrobenzisothiazinyl, benzopyranyl,benzothiopyranyl, coumarinyl, isocoumarinyl, chromonyl, chromanonyl,tetrahydroquinolinyl, dihydroquinolinyl, dihydroquinolinonyl,dihydroisoquinolinonyl, dihydrocoumarinyl, dihydroisocoumarinyl,isoindolinonyl, benzodioxanyl, benzoxazolinonyl, pyridinyl-N-oxide,pyrrolyl N-oxide, pyrimidinyl N-oxide, pyridazinyl N-oxide, pyrazinylN-oxide, quinolinyl N-oxide, indolyl N-oxide, indolinyl N-oxide,isoquinolyl N-oxide, quinazolinyl N-oxide, quinoxalinyl N-oxide,phthalazinyl N-oxide, imidazolyl N-oxide, isoxazolyl N-oxide, oxazolylN-oxide, thiazolyl N-oxide, indolizinyl N-oxide, indazolyl N-oxide,benzothiazolyl N-oxide, benzimidazolyl N-oxide, pyrrolyl N-oxide,oxadiazolyl N-oxide, thiadiazolyl N-oxide, triazolyl N-oxide, tetrazolylN-oxide, benzothiopyranyl S-oxide, benzothiopyranyl S,S-dioxide,imidazopyrazolyl, quinazolinonyl, pyrazopyridyl, benzooxadiazolyl,dihydropyrimidinonyl, and dihydrobenzfuranonyl,

[0357] where the R_(N-heteroaryl) group is bonded by any atom of theparent R_(N-heteroaryl) group substituted by hydrogen such that the newbond to the R_(N-heteroaryl) group replaces the hydrogen atom and itsbond, where heteroaryl is optionally substituted with one, two, three,or four of:

[0358] (1) C₁-C₆ alkyl, optionally substituted with one, two or threesubstituents selected from the group consisting of C₁-C₃ alkyl, —F, —Cl,—Br, —I, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b),

[0359] (2) —OH,

[0360] (3) —NO₂,

[0361] (4) —F, —Cl, —Br, —I,

[0362] (5) —CO₂H,

[0363] (6) —C≡N,

[0364] (7) —(CH₂)₀₋₄—CO—NR_(N-2)R_(N-3),

[0365] (8) —(CH₂)₀₋₄—CO-(C₁-C₁₂ alkyl),

[0366] (9) —(CH₂)₀₋₄—CO-(C₂-C₁₂ alkenyl),

[0367] (10) —(CH₂)₀₋₄—CO-(C₂-C₁₂ alkynyl),

[0368] (11) —(CH₂)₀₋₄—CO-(C₃-C₈ cycloalkyl),

[0369] (12) —(CH₂)₀₋₄—CO—R_(1-aryl),

[0370] (13) —(CH₂)₀₋₄—CO—R_(1-heteroaryl),

[0371] (14) —(CH₂)₀₋₄—CO—R_(1-heterocycle),

[0372] (15) —(CH₂)₀₋₄—CO—R_(N-4)

[0373] (16) —(CH₂)₀₋₄—CO—O—R_(N-5)

[0374] (17) —(CH₂)₀₋₄—SO₂—NR_(N-2)R_(N-3),

[0375] (18) —(CH₂)₀₋₄—SO-(C₁-C₈ alkyl),

[0376] (19) —(CH₂)₀₋₄—SO₂-(C₁-C₁₂ alkyl),

[0377] (20) —(CH₂)₀₋₄—SO₂-(C₃-C₈ cycloalkyl),

[0378] (21) —(CH₂)₀₋₄—N(H or R_(N-5))—CO—O—R_(N-5),

[0379] (22) —(CH₂)₀₋₄—N(H or R_(N-5))—CO—N(R_(N-5))₂,

[0380] (23) —(CH₂)₀₋₄—N—CS—N(R_(N-5))₂,

[0381] (24) —(CH₂)₀₋₄—N(—H or R_(N-5))—CO—R_(N-2),

[0382] (25) —(CH₂)₀₋₄—NR_(N-2)R_(N-3),

[0383] (26) —(CH₂)₀₋₄—R_(N-4),

[0384] (27) —(CH₂)₀₋₄—O—CO-(C₁-C₆ alkyl),

[0385] (28) —(CH₂)₀₋₄—O—P(O)—(OR₁₀₀)₂,

[0386] (29) —(CH₂)₀₋₄—O—CO—N(R_(N-5))₂,

[0387] (30) —(CH₂)₀₋₄—O—CS—N(R_(N-5))₂,

[0388] (31) —(CH₂)₀₋₄—O—(R_(N-5)),

[0389] (32) —(CH₂)₀₋₄—O—(R_(N-5))—COOH,

[0390] (33) —(CH₂)₀₋₄—S—(R_(N-5)),

[0391] (34) —(CH₂)₀₋₄—O-(C₁-C₆ alkyl optionally substituted with one,two, three, four, or five of —F),

[0392] (35) C₃-C₈ cycloalkyl,

[0393] (36) C₂-C₆ alkenyl optionally substituted with C₁-C₃ alkyl, —F,—Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, or —NR_(1-a)R_(1-b),

[0394] (37) C₂-C₆ alkynyl optionally substituted with C₁-C₃ alkyl, —F,—Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, or —NR_(1-a)R_(1-b),

[0395] (38) —(CH₂)₀₋₄—N(—H or R_(N-5))—SO₂—R_(N-2),

[0396] (39) —(CH₂)₁₋₄—C₃-C₈ cycloalkyl,

[0397] (C) R_(N-aryl)—W—R_(N-aryl),

[0398] (D) R_(N-aryl)—W—R_(N-heteroaryl),

[0399] (E) R_(N-aryl)—W—R_(1-heterocycle),,

[0400] (F) R_(N-heteroaryl)—W—R_(N-aryl),

[0401] (G) R_(N-heteroaryl)—W—R_(N-heteroaryl),

[0402] (H) R_(N-heteroaryl)—W—R_(N-1-heterocycle),

[0403] (I) R_(N-heterocycle)—W—R_(N-aryl),

[0404] (J) R_(N-heterocycle)—W—R_(N-heteroaryl),

[0405] (K) R_(N-heterocycle)—W—R_(N-1-heterocycle),

[0406] where W is

[0407] (1) —(CH₂)₁₋₄—,

[0408] (2) —O—,

[0409] (3) —S(O)₀₋₂—,

[0410] (4) —N(R_(N-5))—,

[0411] (5) —CO—; or

[0412] (6) a bond;

[0413] (II) —CO-(C₁-C₁₀ alkyl) wherein the alkyl is optionallysubstituted with one two or three substituents independently selectedfrom the group consisting of:

[0414] (A) —OH,

[0415] (B) —C₁-C₆ alkoxy,

[0416] (C) —C₁-C₆ thioalkoxy,

[0417] (D) —CO—O—R_(N-8) where

[0418] R_(N-8) at each occurrence is independently —H, C₁-C₆ alkyl or-phenyl,

[0419] (E) —CO—NR_(N-2)R_(N-3),

[0420] (F) —CO—R_(N-4),

[0421] (G) —SO₂-(C₁-C₈ alkyl),

[0422] (H) —SO₂—NR_(N-2)R_(N-3),

[0423] (I) —NH—CO-(C₁-C₆ alkyl),

[0424] (J) —NH—CO—O—R_(N-8),

[0425] (K) —NR_(N-2)R_(N-3),

[0426] (L) —R_(N-4),

[0427] (M) —O—CO-(C₁-C₆ alkyl),

[0428] (N) —O—CO—NR_(N-8)R_(N-8),

[0429] (O) —O-(C₁-C₅ alkyl)-COOH,

[0430] (P) —O-(C₁-C₆ alkyl optionally substituted with one, two, orthree of —F, —Cl, —Br, —I),

[0431] (Q) —NH—SO₂-(C₁-C₆ alkyl),

[0432] (R) halogen,

[0433] (S) —N(H or R_(N-5))—SO₂—R_(N-2),

[0434] (T) —N(H or R_(N-5))—CO—(R_(N-2)), and

[0435] (U) —SO₂—R_(N-2),

[0436] (III) —CO-(C₁-C₆ alkyl)-O-(C₁-C₆ alkyl) wherein each alkyl isunsubstituted or independently substituted with one, two, or threesubstituents selected from the group consisting of

[0437] (A) —OH,

[0438] (B) —C₁-C₆ alkoxy,

[0439] (C) —C₁-C₆ thioalkoxy,

[0440] (D) —CO—O—R_(N-8),

[0441] (E) —CO—NR_(N-2)R_(N-3),

[0442] (F) —CO—R_(N-4),

[0443] (G) —SO₂—(C₁-C₈ alkyl),

[0444] (H) —SO₂—NR_(N-2)R_(N-3),

[0445] (I) —NH—CO-(C₁-C₆ alkyl),

[0446] (J) —NH—CO—O—R_(N-8),

[0447] (K) —NR_(N-2)R_(N-3),

[0448] (L) —R_(N-4),

[0449] (M) —O—CO—(C₁-C₆ alkyl),

[0450] (N) —O—CO—NR_(N-8)R_(N-8),

[0451] (O) —O-(C₁-C₅ alkyl)-CO₂H,

[0452] (P) —O-(C₁-C₆ alkyl optionally substituted with one, two, orthree groups that are independently —F, —Cl, —Br, or —I),

[0453] (Q) —NH—SO₂-(C₁-C₆ alkyl),

[0454] (R) halogen,

[0455] (S) —N(H or R_(N-5))—SO₂—R_(N-2),

[0456] (T) —N(H or R_(N-5))—CO—(R_(N-2)), and

[0457] (U) —SO₂—R_(N-2),

[0458] (IV) —CO-(C₁-C₆ alkyl)-S-(C₁-C₆ alkyl) wherein each alkyl isunsubstituted or substituted with one, two, or three of substituentsindependently selected from the group consisting of:

[0459] (A) —OH,

[0460] (B) —C₁-C₆ alkoxy,

[0461] (C) —C₁-C₆ thioalkoxy,

[0462] (D) —CO—O—R_(N-8),

[0463] (E) —CO—NR_(N-2)R_(N-3),

[0464] (F) —CO—R_(N-4),

[0465] (G) —SO₂—(C₁-C₈ alkyl),

[0466] (H) —SO₂—NR_(N-2)R_(N-3),

[0467] (I) —NH—CO-(C₁-C₆ alkyl),

[0468] (J) —NH—CO—O—R_(N-8),

[0469] (K) —NR_(N-2)R_(N-3),

[0470] (L) —R_(N-4),

[0471] (M) —O—CO-(C₁-C₆ alkyl),

[0472] (N) —O—CO—NR_(N-8)R_(N-8),

[0473] (O) —O-(C₁-C₅ alkyl)-COOH,

[0474] (P) —O-(C₁-C₆ alkyl optionally substituted with one, two, orthree groups that are independently —F, —Cl, —Br, or —I),

[0475] (Q) —NH—SO₂-(C₁-C₆ alkyl),

[0476] (R) halogen,

[0477] (S) —N(H or R_(N-5))—SO₂—R_(N-2),

[0478] (T) —N(H or R_(N-5))—CO—(R_(N-2)), and

[0479] (U) —SO₂—R_(N-2),

[0480] (V)—CO—CH(—(CH₂)₀₋₂—O—R_(N-10))—(CH₂)₀₋₂—R_(N-aryl)/R_(N-heteroaryl))wherein

[0481] R_(N-10) is selected from the group consisting of:

[0482] (A) —H,

[0483] (B) C₁-C₆ alkyl,

[0484] (C) C₃-C₈ cycloalkyl,

[0485] (D) C₂-C₆ alkenyl with one double bond,

[0486] (E) C₂-C₆ alkynyl with one triple bond,

[0487] (F) R_(1-aryl),

[0488] (G) R_(N-heteroaryl),

[0489] (H) R_(N-heterocycle),

[0490] (VI) —CO-(C₃-C₈ cycloalkyl) where the cycloalkyl group isoptionally substituted with one or two substituents independentlyselected from the group consisting of:

[0491] (A) —(CH₂)₀₋₄—OH,

[0492] (B) —(CH₂)₀₋₄—C₁-C₆ alkoxy,

[0493] (C) —(CH₂)₀₋₄—C₁-C₆ thioalkoxy,

[0494] (D) —(CH₂)₀₋₄—CO—O—R_(N-8),

[0495] (E) —(CH₂)₀₋₄—CO—NR_(N-2)R_(N-3),

[0496] (F) —(CH₂)₀₋₄—CO—R_(N-4),

[0497] (G) —(CH₂)₀₋₄—SO₂-(C₁-C₈ alkyl),

[0498] (H) —(CH₂)₀₋₄—SO₂—NR_(N-2)R_(N-3),

[0499] (I) —(CH₂)₀₋₄—NH—CO-(C₁-C₆ alkyl),

[0500] (J) —NH—CO—O—R_(N-8),

[0501] (K) —(CH₂)₀₋₄—NR_(N-2)R_(N-3),

[0502] (L) —(CH₂)₀₋₄—R_(N-4),

[0503] (M) —O—CO-(C₁-C₆ alkyl),

[0504] (N) —O—CO—NR_(N-8)R_(N-8),

[0505] (O) —O-(C₁-C₆ alkyl)-CO₂H,

[0506] (p) —O-(C₁-C₆ alkyl optionally substituted with one, two, orthree groups that are independently selected from —F, —Cl, —Br, and —I),

[0507] (Q) —NH—SO₂-(C₁-C₆ alkyl),

[0508] (R) halogen,

[0509] (S) —N(H or R_(N-5))—SO₂—R_(N-2), and

[0510] (T) —N(H or R_(N-5))—CO—(R_(N-2)), and

[0511] (U) —SO₂—R_(N-2);

[0512] where R₁ and R₂ are independently H, aryl, heteroaryl, or

[0513] (I) C₁-C₆ alkyl, optionally substituted with one, two or threesubstituents selected from the group consisting of C₁-C₃ alkyl, C₁-C₇alkyl (optionally substituted with C₁-C₃ alkyl and C₁-C₃ alkoxy), —F,—Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, —NR_(1-a)R_(1-b) whereR_(1-a) and R_(1-b) are independently —H or C₁-C₆ alkyl, and —OC═ONR_(1-a)R_(1-b),

[0514] (II) —CH₂—S(O)₀₋₂-(C₁-C₆ alkyl),

[0515] (III) —CH₂—CH₂—S(O)₀₋₂-(C₁-C₆ alkyl),

[0516] (IV) C₂-C₆ alkenyl with one or two double bonds, optionallysubstituted with one, two or three substituents selected from the groupconsisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and—NR_(1-a)R_(1-b),

[0517] (V) C₂-C₆ alkynyl with one or two triple bonds, optionallysubstituted with one, two or three substituents selected from the groupconsisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and—NR_(1-a)R_(1-b),

[0518] (VI) —(CH₂)_(n1)—(R_(1-aryl)) where n₁ is zero or one and whereR_(1-aryl) is phenyl, 1-naphthyl, 2-naphthyl and indanyl, indenyl,dihydronaphthalyl, or tetralinyl optionally substituted with one, two,three or four of the following substituents on the aryl ring:

[0519] (A) C₁-C₆ alkyl optionally substituted with one, two or threesubstituents selected from the group consisting of C₁-C₃ alkyl, —F, —Cl,—Br, —I, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b),

[0520] (B) C₂-C₆ alkenyl with one or two double bonds, optionallysubstituted with one, two or three substituents selected from the groupconsisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and—NR_(1-a)R_(1-b),

[0521] (C) C₂-C₆ alkynyl with one or two triple bonds, optionallysubstituted with one, two or three substituents selected from the groupconsisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and—NR_(1-a)R_(1-b),

[0522] (D) —F, Cl, —Br or —I,

[0523] (F) —C₁-C₆ alkoxy optionally substituted with one, two or threeof —F,

[0524] (G) —NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) are as definedbelow,

[0525] (H) —OH,

[0526] (I) —C≡N,

[0527] (J) C₃-C₇ cycloalkyl, optionally substituted with one, two orthree substituents selected from the group consisting of —F, —Cl, —OH,—SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b),

[0528] (K) —CO-(C₁-C₄ alkyl),

[0529] (L) —SO₂—NR_(1-a)R_(1-b),

[0530] (M) —CO—NR_(1-a)R_(1-b),

[0531] (N) —SO₂—(C₁-C₄ alkyl),

[0532] (VII) —(CH₂)_(n1)—(R_(1-heteroaryl)) where n₁ is as defined aboveand where R_(1-heteroaryl) is selected from the group consisting of:

[0533] pyridinyl, pyrimidinyl, quinolinyl, benzothienyl, indolyl,indolinyl, pryidazinyl, pyrazinyl, isoindolyl, isoquinolyl,quinazolinyl, quinoxalinyl, phthalazinyl, imidazolyl, isoxazolyl,pyrazolyl, oxazolyl, thiazolyl, indolizinyl, indazolyl, benzothiazolyl,benzimidazolyl, benzofuranyl, furanyl, thienyl, pyrrolyl, oxadiazolyl,thiadiazolyl, triazolyl, tetrazolyl, oxazolopyridinyl, imidazopyridinyl,isothiazolyl, naphthyridinyl, cinnolinyl, carbazolyl, beta-carbolinyl,isochromanyl, chromanyl, tetrahydroisoquinolinyl, isoindolinyl,isobenzotetrahydrofuranyl, isobenzotetrahydrothienyl, isobenzothienyl,benzoxazolyl, pyridopyridinyl, benzotetrahydrofuranyl,benzotetrahydrothienyl, purinyl, benzodioxolyl, triazinyl, phenoxazinyl,phenothiazinyl, pteridinyl, benzothiazolyl, imidazopyridinyl,imidazothiazolyl, dihydrobenzisoxazinyl, benzisoxazinyl, benzoxazinyl,dihydrobenzisothiazinyl, benzopyranyl, benzothiopyranyl, coumarinyl,isocoumarinyl, chromonyl, chromanonyl, pyridinyl-N-oxide,tetrahydroquinolinyl, dihydroquinolinyl, dihydroquinolinonyl,dihydroisoquinolinonyl, dihydrocoumarinyl, dihydroisocoumarinyl,isoindolinonyl, benzodioxanyl, benzoxazolinonyl, pyrrolyl N-oxide,pyrimidinyl N-oxide, pyridazinyl N-oxide, pyrazinyl N-oxide, quinolinylN-oxide, indolyl N-oxide, indolinyl N-oxide, isoquinolyl N-oxide,quinazolinyl N-oxide, quinoxalinyl N-oxide, phthalazinyl N-oxide,imidazolyl N-oxide, isoxazolyl N-oxide, oxazolyl N-oxide, thiazolylN-oxide, indolizinyl N-oxide, indazolyl N-oxide, benzothiazolyl N-oxide,benzimidazolyl N-oxide, pyrrolyl N-oxide, oxadiazolyl N-oxide,thiadiazolyl N-oxide, triazolyl N-oxide, tetrazolyl N-oxide,benzothiopyranyl S-oxide, benzothiopyranyl S,S-dioxide,

[0534] where the R_(1-heteroaryl) group is bonded to —(CH₂)_(n1)— by anyring atom of the parent R_(N-heteroaryl) group substituted by hydrogensuch that the new bond to the R_(1-heteroaryl) group replaces thehydrogen atom and its bond, where heteroaryl is optionally substitutedwith one, two, three or four of:

[0535] (1) C₁-C₆ alkyl optionally substituted with one, two or threesubstituents selected from the group consisting of C₁-C₃ alkyl, —F, —Cl,—Br, —I, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b),

[0536] (2) C₂-C₆ alkenyl with one or two double bonds, optionallysubstituted with one, two or three substituents selected from the groupconsisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and—NR_(1-a)R_(1-b),

[0537] (3) C₂-C₆ alkynyl with one or two triple bonds, optionallysubstituted with one, two or three substituents selected from the groupconsisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and—NR_(1-a)R_(1-b),

[0538] (4) —F, Cl, —Br or —I,

[0539] (6) —C₁-C₆ alkoxy optionally substituted with one, two, or threeof —F,

[0540] (7) —NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) are as definedbelow,

[0541] (8) —OH,

[0542] (9) —C≡N,

[0543] (10) C₃-C₇ cycloalkyl, optionally substituted with one, two orthree substituents selected from the group consisting of —F, —Cl, —OH,—SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b),

[0544] (11) —CO-(C₁-C₄ alkyl),

[0545] (12) —SO₂—NR_(1-a)R_(1-b),

[0546] (13) —CO—NR_(1-a)R_(1-b), or

[0547] (14) —SO₂-(C₁-C₄ alkyl), with the proviso that when n₁ is zeroR_(1-heteroaryl) is not bonded to the carbon chain by nitrogen, or

[0548] (VIII) —(CH₂)_(n1)—(R_(1-heterocycle)) where n₁ is as definedabove and R_(1-heterocycle) is selected from the group consisting of:

[0549] morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide,thiomorpholinyl S,S-dioxide, piperazinyl, homopiperazinyl, pyrrolidinyl,pyrrolinyl, tetrahydropyranyl, piperidinyl, tetrahydrofuranyl,tetrahydrothienyl, homopiperidinyl, homomorpholinyl, homomorpholinylS-oxide, homothiomorpholinyl S,S-dioxide, oxazolidinonyl,dihydropyrazolyl, dihydropyrrolyl dihydropyrazinyl dihydropyridinyldihydropyrimidinyl, dihydrofuryl, dihydropyranyl, tetrahydrothienylS-oxide, tetrahydrothienyl S,S-dioxide, homothiomorpholinyl S-oxide,

[0550] where the R_(1-heterocycle) group is bonded by any atom of theparent R_(1-heterocycle) group substituted by hydrogen such that the newbond to the R_(1-heterocycle) group replaces the hydrogen atom and itsbond, where heterocycle is optionally substituted with one, two, threeor four:

[0551] (1) C₁-C₆ alkyl optionally substituted with one, two or threesubstituents selected from the group consisting of C₁-C₃ alkyl, —F, —Cl,—Br, —I, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b),

[0552] (2) C₂-C₆ alkenyl with one or two double bonds, optionallysubstituted with one, two or three substituents selected from the groupconsisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and—NR_(1-a)R_(1-b),

[0553] (3) C₂-C₆ alkynyl with one or two triple bonds, optionallysubstituted with one, two or three substituents selected from the groupconsisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and—NR_(1-a)R_(1-b),

[0554] (4) —F, Cl, —Br, or —I,

[0555] (5) C₁-C₆ alkoxy,

[0556] (6) —C₁-C₆ alkoxy optionally substituted with one, two, or three—F,

[0557] (7) —NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) are as definedbelow,

[0558] (8) —OH,

[0559] (9) —C≡N,

[0560] (10) C₃-C₇ cycloalkyl, optionally substituted with one, two orthree substituents selected from the group consisting of —F, —Cl, —OH,—SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b),

[0561] (11) —CO-(C₁-C₄ alkyl),

[0562] (12) —SO₂—NR_(1-a)R_(1-b),

[0563] (13) —CO—NR_(1-a)R_(1-b),

[0564] (14) —SO₂-(C₁-C₄ alkyl),

[0565] (15) ═O, with the proviso that when n₁ is zero R_(1-heterocycle)is not bonded to the carbon chain by nitrogen; and

[0566] where R₂₀ is H or C₁₋₆ alkyl or alkenyl.

[0567] In alternative broad aspect, the invention provides compounds offormula I, wherein each of the R₂ groups (I)-(VIII) is attached to thenitrogen carrying R₂₀ by —Z—, wherein Z is —C(O)—, —CO₂ or —SO₂—.

[0568] The invention also provides compounds, compositions, kits, andmethods for inhibiting beta-secretase-mediated cleavage of amyloidprecursor protein (APP). More particularly, the compounds, compositions,and methods of the invention are effective to inhibit the production ofA-beta peptide and to treat and/or prevent any human or veterinarydisease or condition associated with a pathological form of A-betapeptide.

[0569] The invention also include methods of treating a patient who has,or in preventing a patient from getting, a disease or condition selectedfrom the group consisting of Alzheimer's disease, for helping prevent ordelay the onset of Alzheimer's disease, for treating patients with mildcognitive impairment (MCI) and preventing or delaying the onset ofAlzheimer's disease in those who would progress from MCI to AD, fortreating Down's syndrome, for treating humans who have HereditaryCerebral Hemorrhage with Amyloidosis of the Dutch-Type, for treatingcerebral amyloid angiopathy and preventing its potential consequences,i.e. single and recurrent lobar hemorrhages, for treating otherdegenerative dementias, including dementias of mixed vascular anddegenerative origin, dementia associated with Parkinson's disease,frontotemporal dementias with parkinsonism (FTDP), dementia associatedwith progressive supranuclear palsy, dementia associated with corticalbasal degeneration, or diffuse Lewy body type of Alzheimer's disease andwho is in need of such treatment, which includes administration of atherapeutically effective amount of a compound of formula (I), or apharmaceutically acceptable salt or ester thereof.

[0570] The compounds of the invention possess beta-secretase inhibitoryactivity. The inhibitory activities of the compounds of the invention isreadily demonstrated, for example, using one or more of the assaysdescribed herein or known in the art.

[0571] In an embodiment, this method of treatment can be used where thedisease is Alzheimer's disease.

[0572] In an embodiment, this method of treatment can help prevent ordelay the onset of Alzheimer's disease.

[0573] In an embodiment, this method of treatment can be used where thedisease is mild cognitive impairment.

[0574] In an embodiment, this method of treatment can be used where thedisease is Down's syndrome.

[0575] In an embodiment, this method of treatment can be used where thedisease is Hereditary Cerebral Hemorrhage with Amyloidosis of theDutch-Type.

[0576] In an embodiment, this method of treatment can be used where thedisease is cerebral amyloid angiopathy.

[0577] In an embodiment, this method of treatment can be used where thedisease is degenerative dementias.

[0578] In an embodiment, this method of treatment can be used where thedisease is diffuse Lewy body type of Alzheimer's disease.

[0579] In an embodiment, this method of treatment can treat an existingdisease.

[0580] In an embodiment, this method of treatment can prevent a diseasefrom developing.

[0581] In an embodiment, this method of treatment can employtherapeutically effective amounts: for oral administration from about0.1 mg/day to about 1,000 mg/day; for parenteral, sublingual,intranasal, intrathecal administration from about 0.5 to about 100mg/day; for depo administration and implants from about 0.5 mg/day toabout 50 mg/day; for topical administration from about 0.5 mg/day toabout 200 mg/day; for rectal administration from about 0.5 mg to about500 mg.

[0582] In an embodiment, this method of treatment can employtherapeutically effective amounts: for oral administration from about 1mg/day to about 100 mg/day; and for parenteral administration from about5 to about 50 mg daily.

[0583] In an embodiment, this method of treatment can employtherapeutically effective amounts for oral administration from about 5mg/day to about 50 mg/day.

[0584] The invention also includes a pharmaceutical composition whichincludes a compound of formula (I), or a pharmaceutically acceptablesalt or ester thereof.

[0585] The invention also includes the use of a compound of formula (I),or a pharmaceutically acceptable salt or ester thereof, for themanufacture of a medicament for use in treating a patient who has, or inpreventing a patient from getting, a disease or condition selected fromthe group consisting of Alzheimer's disease, for helping prevent ordelay the onset of Alzheimer's disease, for treating patients with mildcognitive impairment (MCI) and preventing or delaying the onset ofAlzheimer's disease in those who would progress from MCI to AD, fortreating Down's syndrome, for treating humans who have HereditaryCerebral Hemorrhage with Amyloidosis of the Dutch-Type, for treatingcerebral amyloid angiopathy and preventing its potential consequences,i.e. single and recurrent lobar hemorrhages, for treating otherdegenerative dementias, including dementias of mixed vascular anddegenerative origin, dementia associated with Parkinson's disease,dementia associated with progressive supranuclear palsy, dementiaassociated with cortical basal degeneration, diffuse Lewy body type ofAlzheimer's disease and who is in need of such treatment.

[0586] In an embodiment, this use of a compound of the formulahereinabove can be employed where the disease is Alzheimer's disease.

[0587] In an embodiment, this use of a compound of the formulahereinabove can help prevent or delay the onset of Alzheimer's disease.

[0588] In an embodiment, this use of a compound of the formulahereinabove can be employed where the disease is mild cognitiveimpairment.

[0589] In an embodiment, this use of a compound of the formulahereinabove can be employed where the disease is Down's syndrome.

[0590] In an embodiment, this use of a compound of the formulahereinabove can be employed where the disease is Hereditary CerebralHemorrhage with Amyloidosis of the Dutch-Type.

[0591] In an embodiment, this use of a compound of the formulahereinabove can be employed where the disease is cerebral amyloidangiopathy.

[0592] In an embodiment, this use of a compound of the formulahereinabove can be employed where the disease is degenerative dementias.

[0593] In an embodiment, this use of a compound of the formulahereinabove can be employed where the disease is diffuse Lewy body typeof Alzheimer's disease.

[0594] In an embodiment, this use of a substituted amine employs apharmaceutically acceptable salt selected from the group consisting ofsalts of the following acids hydrochloric, hydrobromic, hydroiodic,nitric, sulfuric, phosphoric, citric, methanesulfonic,CH₃—(CH₂)_(n)—COOH where n is 0 through 4, HOOC—(CH₂)_(n)—COOH where nis as defined above, HOOC—CH═CH—COOH, and phenyl-COOH.

[0595] The invention also includes methods for inhibiting beta-secretaseactivity, for inhibiting cleavage of amyloid precursor protein (APP), ina reaction mixture, at a site between Met596 and Asp597, numbered forthe APP-695 amino acid isotype, or at a corresponding site of an isotypeor mutant thereof; for inhibiting production of amyloid beta peptide (Abeta) in a cell; for inhibiting the production of beta-amyloid plaque inan animal; and for treating or preventing a disease characterized bybeta-amyloid deposits in the brain. These methods each includeadministration of a therapeutically effective amount of a compound offormula (I), or a pharmaceutically acceptable salt or ester thereof.

[0596] The invention also includes a method for inhibitingbeta-secretase activity, including exposing said beta-secretase to aneffective inhibitory amount of a compound of formula, or apharmaceutically acceptable salt or ester thereof.

[0597] In an embodiment, this method employs a compound that inhibits50% of the enzyme's activity at a concentration of less than 50micromolar.

[0598] In an embodiment, this method employs a compound that inhibits50% of the enzyme's activity at a concentration of 10 micromolar orless.

[0599] In an embodiment, this method employs a compound that inhibits50% of the enzyme's activity at a concentration of 1 micromolar or less.

[0600] In an embodiment, this method employs a compound that inhibits50% of the enzyme's activity at a concentration of 10 nanomolar or less.

[0601] In an embodiment, this method includes exposing saidbeta-secretase to said compound in vitro.

[0602] In an embodiment, this method includes exposing saidbeta-secretase to said compound in a cell.

[0603] In an embodiment, this method includes exposing saidbeta-secretase to said compound in a cell in an animal.

[0604] In an embodiment, this method includes exposing saidbeta-secretase to said compound in a human.

[0605] The invention also includes a method for inhibiting cleavage ofamyloid precursor protein (APP), in a reaction mixture, at a sitebetween Met596 and Asp597, numbered for the APP-695 amino acid isotype;or at a corresponding site of an isotype or mutant thereof, includingexposing said reaction mixture to an effective inhibitory amount of acompound of formula (I), or a pharmaceutically acceptable salt or esterthereof.

[0606] In an embodiment, this method employs a cleavage site:

[0607] between Met652 and Asp653, numbered for the APP-751 isotype;

[0608] between Met 671 and Asp 672, numbered for the APP-770 isotype;

[0609] between Leu596 and Asp597 of the APP-695 Swedish Mutation;

[0610] between Leu652 and Asp653 of the APP-751 Swedish Mutation; or

[0611] between Leu671 and Asp672 of the APP-770 Swedish Mutation.

[0612] In an embodiment, this method exposes said reaction mixture invitro.

[0613] In an embodiment, this method exposes said reaction mixture in acell.

[0614] In an embodiment, this method exposes said reaction mixture in ananimal cell.

[0615] In an embodiment, this method exposes said reaction mixture in ahuman cell.

[0616] The invention also includes a method for inhibiting production ofamyloid beta peptide (A beta) in a cell, including administering to saidcell an effective inhibitory amount of a compound of formula (I) , or apharmaceutically acceptable salt or ester thereof.

[0617] In an embodiment, this method includes administering to ananimal.

[0618] In an embodiment, this method includes administering to a human.

[0619] The invention also includes a method for inhibiting theproduction of beta-amyloid plaque in an animal, including administeringto said animal an effective inhibitory amount of a compound of formula(I) , or a pharmaceutically acceptable salt or ester thereof.

[0620] In an embodiment, this method includes administering to a human.

[0621] The invention also includes a method for treating or preventing adisease characterized by beta-amyloid deposits in the brain includingadministering to a patient an effective therapeutic amount of ahydroxyethylene compound of formula (I) or a pharmaceutically acceptablesalt or ester thereof.

[0622] In an embodiment, this method employs a compound that inhibits50% of the enzyme's activity at a concentration of less than 50micromolar.

[0623] In an embodiment, this method employs a compound that inhibits50% of the enzyme's activity at a concentration of 10 micromolar orless.

[0624] In an embodiment, this method employs a compound that inhibits50% of the enzyme's activity at a concentration of 1 micromolar or less.

[0625] In an embodiment, this method employs a compound that inhibits50% of the enzyme's activity at a concentration of 10 nanomolar or less.

[0626] In an embodiment, this method employs a compound at a therapeuticamount in the range of from about 0.1 to about 1000 mg/day.

[0627] In an embodiment, this method employs a compound at a therapeuticamount in the range of from about 15 to about 1500 mg/day.

[0628] In an embodiment, this method employs a compound at a therapeuticamount in the range of from about 1 to about 100 mg/day.

[0629] In an embodiment, this method employs a compound at a therapeuticamount in the range of from about 5 to about 50 mg/day.

[0630] In an embodiment, this method can be used where said disease isAlzheimer's disease.

[0631] In an embodiment, this method can be used where said disease isMild Cognitive Impairment, Down's Syndrome, or Hereditary CerebralHemorrhage with Amyloidosis of the Dutch Type.

[0632] The invention also includes a composition includingbeta-secretase complexed with a compound of formula (I), or apharmaceutically acceptable salt or ester thereof.

[0633] The invention also includes a method for producing abeta-secretase complex including exposing beta-secretase to a compoundof formula (I), or a pharmaceutically acceptable salt or ester thereof,in a reaction mixture under conditions suitable for the production ofsaid complex.

[0634] In an embodiment, this method employs exposing in vitro.

[0635] In an embodiment, this method employs a reaction mixture that isa cell.

[0636] The invention also includes a component kit including componentparts capable of being assembled, in which at least one component partincludes a compound of formula I enclosed in a container.

[0637] In an embodiment, this component kit includes lyophilizedcompound, and at least one further component part includes a diluent.

[0638] The invention also includes a container kit including a pluralityof containers, each container including one or more unit dose of acompound of formula (I), or a pharmaceutically acceptable salt or esterthereof.

[0639] In an embodiment, this container kit includes each containeradapted for oral delivery and includes a tablet, gel, or capsule.

[0640] In an embodiment, this container kit includes each containeradapted for parenteral delivery and includes a depot product, syringe,ampoule, or vial.

[0641] In an embodiment, this container kit includes each containeradapted for topical delivery and includes a patch, medipad, ointment, orcream.

[0642] The invention also includes an agent kit including a compound offormula (I), or a pharmaceutically acceptable salt or ester thereof; andone or more therapeutic agent selected from the group consisting of anantioxidant, an anti- inflammatory, a gamma secretase inhibitor, aneurotrophic agent, an acetyl cholinesterase inhibitor, a statin, an Abeta peptide, and an anti-A beta antibody.

[0643] The invention also includes a composition including: a compoundof formula (I), or a pharmaceutically acceptable salt or ester thereof;and an inert diluent or edible carrier.

[0644] In an embodiment, this composition includes a carrier that is anoil.

[0645] The invention also includes a composition including: a compoundof formula (I), or a pharmaceutically acceptable salt or ester thereof;and a binder, excipient, disintegrating agent, lubricant, or gildant.

[0646] The invention also includes a composition including: a compoundof formula (I), or a pharmaceutically acceptable salt or ester thereof;disposed in a cream, ointment, or patch.

DETAILED DESCRIPTION OF THE INVENTION

[0647] As noted above, the invention provides compounds of formula I:

[0648] where R_(N), R_(C), R₁, R₂ and R₂₀ are as defined above, andpharmaceutically acceptable salts and esters thereof.

[0649] In a preferred embodiment, the invention provides for compoundsof formula II:

[0650] or a pharmaceutically acceptable salt thereof,

[0651] where Rc is

[0652] (I) —C₁-C₁₀ alkyl optionally substituted with one, two or threegroups independently selected from the group consisting of C₁-C₃ alkyl,halogen, —OH, —SH, —C≡N, —CF₃, C₁-C₆ alkoxy, —O-phenyl,—NR_(1-a)R_(1-b), —OC═O NR_(1-a)R_(1-b), —S(═O)₀₋₂ R_(1-a), —NR_(1-a)C═ONR_(1-a)R_(1-b), —C═O NR_(1-a)R_(1-b), and —S(═O)₂ NR_(1-a)R_(1-b)wherein

[0653] R_(1-a) and R_(1-b) at each occurrence are independently H orC₁-C₆ alkyl,

[0654] (II) —(CH₂)₀₋₃—(C₃-C₈) cycloalkyl where cycloalkyl can beoptionally substituted with one, two or three substituents independentlyselected from the group consisting of C₁-C₃ alkyl, halogen, —OH, —SH,—C≡N, —CF₃, C₁-C₆ alkoxy, —O-phenyl, —CO₂H, —CO₂-(C₁-C₄ alkyl) , and—NR_(1-a)R_(1-b)

[0655] (III) —(CR_(c-x)R_(c-y))₀₋₄—R_(c-aryl) where R_(c-x) and R_(c-y)are independently selected from the group consisting of

[0656] —H,

[0657] C₁-C₄ alkyl optionally substituted with 1 or 2 —OH,

[0658] C₁-C₄ alkoxy optionally substituted with 1, 2, or 3 halogen,

[0659] —(CH₂)₀₋₄—C₃-C₈ cycloalkyl,

[0660] C₂-C₆ alkenyl containing one or two double bonds,

[0661] C₂-C₆ alkynyl containing one or two triple bonds, and phenyl,

[0662] or

[0663] R_(c-x) and R_(c-y) are taken together with the carbon to whichthey are attached to form a carbocycle of three, four, five, six orseven carbon atoms, where one carbon atom is optionally replaced by agroup selected from —O—, —S—, —SO₂—, —NR_(N-2)— and R_(c-aryl,) wherein

[0664] R_(c-aryl) is phenyl, which is optionally substituted with 1, 2,or 3 groups that are independently:

[0665] (1) C₁-C₆ alkyl, optionally substituted with one, two or threesubstituents selected from the group consisting of C₁-C₃ alkyl, halogen,—OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b),

[0666] (2) —OH,

[0667] (3) —NO₂,

[0668] (4) halogen,

[0669] (5) —CO₂H,

[0670] (6) —C≡N,

[0671] (7) —(CH₂)₀₋₄—CO—NR_(N) ₂RN₃ where

[0672] R_(N-2) and R_(N-3) are independently selected from the groupconsisting of:

[0673] (a) —H,

[0674] (b) —C₁-C₆ alkyl optionally substituted with one substituentselected from the group consisting of:

[0675] (i) —OH, and

[0676] (ii) —NH₂,

[0677] (c) —C₁-C₆ alkyl optionally substituted with 1, 2, or 3 groupsthat are independently —F, —Cl, —Br, —I, or OH,

[0678] (d) —C₃-C₇ cycloalkyl,

[0679] (e) —(C₁-C₂ alkyl)-(C₃-C₇ cycloalkyl),

[0680] (f) —(C₁-C₆ alkyl)-O-(C₁-C₃ alkyl)

[0681] (g) —C₂-C₆ alkenyl

[0682] (h) —C₂-C₆ alkynyl

[0683] (i) —C₁-C₆ alkyl chain with one double bond and one triple bond,

[0684] (j) —R_(1-aryl) wherein R_(1-aryl) at each occurrence isindependently phenyl, naphthyl, indanyl, indenyl, dihydronaphthyl, ortetralinyl each of which is optionally substituted with 1, 2, 3, or 4groups that are independently:

[0685] (i) C₁-C₆ alkyl optionally substituted with one, two or threesubstituents independently selected from the group consisting of C₁-C₃alkyl, —F, —Cl, —Br, —I, —OH, —SH, —NR_(1-a)R_(1-b), —C≡N, —CF₃, andC₁-C₃ alkoxy,

[0686] (ii) C₂-C₆ alkenyl with one or two double bonds, optionallysubstituted with one, two or three substituents independently selectedfrom the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃alkoxy, and —NR_(1-a)R_(1-b),

[0687] (iii) C₂-C₆ alkynyl optionally substituted with 1, 2, or 3 groupsthat are independently selected from the group consisting of —F, —Cl,—OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b),

[0688] (iv) —F, Cl, —Br and —I,

[0689] (v) —C₁-C₆ alkoxy optionally substituted with 1, 2, or 3 —F,

[0690] (vi) —NR_(N-2)R_(N-3),

[0691] (vii) —OH,

[0692] (viii) —C≡N,

[0693] (ix) C₃-C₇ cycloalkyl, optionally substituted with 1, 2, or 3groups that are selected from the group consisting of —F, —Cl, —OH, —SH,—C≡N, —CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b),

[0694] (x) —CO-(C₁-C₄ alkyl),

[0695] (xi) —SO₂-NR_(1-a)R_(1-b),

[0696] (xii) —CO—NR_(1-a)R_(1-b), or

[0697] (xiii) —SO₂-(C₁-C₄ alkyl)

[0698] (k) —R_(1-heteroaryl) wherein R_(1-heteroaryl) at each occurrenceis independently selected from the group consisting of pyridinyl,pyrimidinyl, quinolinyl, benzothienyl, indolyl, indolinyl, pryidazinyl,pyrazinyl, isoindolyl, isoquinolyl, quinazolinyl, quinoxalinyl,phthalazinyl, imidazolyl, isoxazolyl, pyrazolyl, oxazolyl, thiazolyl,indolizinyl, indazolyl, benzothiazolyl, benzimidazolyl, benzofuranyl,furanyl, thienyl, pyrrolyl, oxadiazolyl, thiadiazolyl, triazolyl,tetrazolyl, oxazolopyridinyl, imidazopyridinyl, isothiazolyl,naphthyridinyl, cinnolinyl, carbazolyl, beta-carbolinyl, isochromanyl,chromanyl, tetrahydroisoquinolinyl, isoindolinyl,isobenzotetrahydrofuranyl, isobenzotetrahydrothienyl, isobenzothienyl,benzoxazolyl, pyridopyridinyl, benzotetrahydrofuranyl,benzotetrahydrothienyl, purinyl, benzodioxolyl, triazinyl, phenoxazinyl,phenothiazinyl, pteridinyl, benzothiazolyl, imidazopyridinyl,imidazothiazolyl, dihydrobenzisoxazinyl, benzisoxazinyl, benzoxazinyl,dihydrobenzisothiazinyl, benzopyranyl, benzothiopyranyl, coumarinyl,isocoumarinyl, chromonyl, chromanonyl, pyridinyl-N-oxide,tetrahydroquinolinyl, dihydroquinolinyl, dihydroquinolinonyl,dihydroisoquinolinonyl, dihydrocoumarinyl, dihydroisocoumarinyl,isoindolinonyl, benzodioxanyl, benzoxazolinonyl, pyrrolyl N-oxide,pyrimidinyl N-oxide, pyridazinyl N-oxide, pyrazinyl N-oxide, quinolinylN-oxide, indolyl N-oxide, indolinyl N-oxide, isoquinolyl N-oxide,quinazolinyl N-oxide, quinoxalinyl N-oxide, phthalazinyl N-oxide,imidazolyl N-oxide, isoxazolyl N-oxide, oxazolyl N-oxide, thiazolylN-oxide, indolizinyl N-oxide, indazolyl N-oxide, benzothiazolyl N-oxide,benzimidazolyl N-oxide, pyrrolyl N-oxide, oxadiazolyl N-oxide,thiadiazolyl N-oxide, triazolyl N-oxide, tetrazolyl N-oxide,benzothiopyranyl S-oxide, and benzothiopyranyl S,S-dioxide,

[0699] where the R_(1-heteroaryl) group is optionally substituted with1, 2, 3, or 4 groups that are independently:

[0700] (i) C₁-C₆ alkyl optionally substituted with 1, 2, or 3 groupsindependently selected from the group consisting of C₁-C₃ alkyl, —F,—Cl, —Br, —I, —OH, —SH, —NR_(1-a)R_(1-b), —C≡N, —CF₃, and C₁-C₃ alkoxy,

[0701] (ii) C₂-C₆ alkenyl optionally substituted with 1, 2, or 3 groupsthat are independently —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and—NR_(1-a)R_(1-b),

[0702] (iii) C₂-C₆ alkynyl optionally substituted with 1, 2, or 3 groupsthat are independently selected from the group consisting of —F, —Cl,—OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b),

[0703] (iv) —F, —Cl, —Br and —I,

[0704] (v) —C₁-C₆ alkoxy optionally substituted with one, two, or three—F,

[0705] (vi) —(CH₂)₀₋₄—NR_(N-2)R_(N-3),

[0706] (vii) —OH,

[0707] (viii) —C≡N,

[0708] (ix) (CH₂)₀₋₄-C₃-C₇ cycloalkyl, optionally substituted with 1, 2,or 3 groups that are independently selected from the group consisting of—F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b),

[0709] (x) (CH₂)₀₋₄—CO-(C₁-C₆ alkyl),

[0710] (xi) (CH₂)₀₋₄—SO₂—NR_(N-2)R_(N-3),

[0711] (xii) (CH₂)₀₋₄—CO—NR_(N-2)R_(N-3),

[0712] (xiii) (CH₂)₀₋₄—SO₂-(C₁-C₆ alkyl),

[0713] (xiv) (CH₂)₀₋₄—N(R_(N-2))—SO₂—, and

[0714] (xv) (CH₂)₀₋₄—N(R_(N-2))—C(O)—,

[0715] (8) —(CH₂)₀₋₄—CO-(C₁-C₁₂ alkyl),

[0716] (9) —(CH₂)₀₋₄—CO-(C₂-C₁₂ alkenyl),

[0717] (10) —(CH₂)₀₋₄—CO-(C₂-C₁₂ alkynyl),

[0718] (11) —(CH₂)₀₋₄—CO-(CH₂)₀₋₄ (C₃-C₇ cycloalkyl)

[0719] (12) —(CH₂)₀₋₄—CO—R_(1-aryl),

[0720] (13) —(CH₂)₀₋₄—CO—R_(1-heteroaryl),

[0721] (14) —(CH₂)₀₋₄—CO—R_(1-heterocycle) wherein

[0722] R_(1-heterocycle) at each occurrence is independently selectedfrom the group consisting of morpholinyl, thiomorpholinyl,thiomorpholinyl S-oxide, thiomorpholinyl S,S-dioxide, piperazinyl,homopiperazinyl, pyrrolidinyl, pyrrolinyl, tetrahydropyranyl,piperidinyl, tetrahydrofuranyl, tetrahydrothienyl, homopiperidinyl,homomorpholinyl, homothiomorpholinyl, homothiomorpholinyl S,S-dioxide,oxazolidinonyl, dihydropyrazolyl, dihydropyrrolyl, dihydropyrazinyl,dihydropyridinyl, dihydropyrimidinyl, dihydrofuryl, dihydropyranyl,tetrahydrothienyl S-oxide, tetrahydrothienyl S,S-dioxide, andhomothiomorpholinyl S-oxide,

[0723] where the R_(1-heterocycle) group is bonded by any atom of theparent R_(1-heterocycle) group substituted by hydrogen such that the newbond to the R_(1-heterocycle) group replaces the hydrogen atom and itsbond, where heterocycle is optionally substituted with 1, 2, 3, or 4groups that are independently:

[0724] (a) C₁-C₆ alkyl optionally substituted with one, two or threesubstituents independently selected from the group consisting of C₁-C₃alkyl, halogen, —OH, —SH, —NR_(1-a)R_(1-b)—C≡N, —CF₃, and C₁-C₃ alkoxy,

[0725] (b) C₂-C₆ alkenyl with one or two double bonds, optionallysubstituted with one, two or three substituents independently selectedfrom the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃alkoxy, and —NR_(1-a)R_(1-b)

[0726] (c) C₂-C₆ alkynyl with one or two triple bonds, optionallysubstituted with one, two or three substituents independently selectedfrom the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃alkoxy, and —NR_(1-a)R_(1-b)

[0727] (d) halogen,

[0728] (e) C₁-C₆ alkoxy,

[0729] (f) —C₁-C₆ alkoxy optionally substituted with one, two, or three—F,

[0730] (g) —NR_(N-2)R_(N-3),

[0731] (h) —OH,

[0732] (i) —C≡N,

[0733] (j) (CH₂)₀₋₄-(C₃-C₇ cycloalkyl), optionally substituted with 1,2, or 3 groups independently selected from the group consisting of —F,—Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b),

[0734] (k) —(CH₂)₀₋₄—CO-(C₁-C₄ alkyl)

[0735] (l) —(CH₂)_(0-4 —SO) ₂—NR_(1-a)R_(1-b),

[0736] (m) —(CH₂)₀₋₄—CO—NR_(1-a)R_(1-b),

[0737] (n) —(CH₂)₀₋₄—SO₂-(C₁-C₆ alkyl), and

[0738] (o) =O,

[0739] (p) —(CH₂)₀₋₄—N(R_(N-2))—SO₂—

[0740] (q) —(CH₂)₀₋₄—N(R_(N-2))—C(O)—

[0741] (15) —(CH₂)₀₋₄—CO—R_(N-4) wherein

[0742] R_(N-4) at each occurrence is independently selected from thegroup consisting of morpholinyl, thiomorpholinyl, pyrrolidinonyl,pyrrolyl, pyrazolyl, thienyl, pyridyl N-oxide, piperazinyl, piperidinyl,homomorpholinyl, homothiomorpholinyl, homothiomorpholinyl S-oxide,homothiomorpholinyl S,S-dioxide, pyrrolinyl and pyrrolidinyl where eachgroup is optionally substituted with 1, 2, 3, or 4 groups that areindependently C₁-C₆ alkyl,

[0743] (16) —(CH₂)₀₋₄—CO₂—R_(N-5) where

[0744] R_(N-5) at each occurrence is independently selected from thegroup consisting of:

[0745] (a) C₁-C₆ alkyl,

[0746] (b) —(CH₂)₀₋₂—(R_(1-aryl))

[0747] (c) C₂-C₆ alkenyl,

[0748] (d) C₂-C₆ alkynyl,

[0749] (e) C₃-C₇ cycloalkyl, and

[0750] (f) —(CH₂)₀₋₄—(R_(1-heteroaryl)),

[0751] (17) —(CH₂)₀₋₄—SO₂—NR_(N-2)R_(N-3)

[0752] (18) —(CH₂)₀₋₄—SO-(C₁-C₈ alkyl),

[0753] (19) —(CH₂)₀₋₄—SO₂-(C₁-C₁₂ alkyl)

[0754] (20) —(CH₂)₀₋₄—SO₂-(C₃-C₇ cycloalkyl)

[0755] (21) —(CH₂)₀₋₄—N(H or R_(N-5))—CO₂—R_(N-5),

[0756] (22) —(CH₂)₀₋₄—N (H or R_(N-5))—CO—N (R_(N-5))₂,

[0757] (23) —(CH₂)₀₋₄—N—CS—N(R_(N-5))₂,

[0758] (24) —(CH₂)₀₋₄—N(—H or R_(N-5))—CO—R_(N-2),

[0759] (25) —(CH₂)₀₋₄—NR_(N-2)R_(N-3),

[0760] (26) —(CH₂)₀₋₄—R_(N-4),

[0761] (27) —(CH₂)₀₋₄—O—CO-(C₁-C₆ alkyl)

[0762] (28) —(CH₂)₀₋₄—O—P(O)—(OR₁₀₀)₂ where R₁₀₀ is independently H orC₁-C₄ alkyl,

[0763] (29) —(CH₂)₀₋₄—O—CO—N(R_(N-5))₂,

[0764] (30) —(CH₂)₀₋₄—O—CS—N(R_(N-5))₂,

[0765] (31) —(CH₂)₀₋₄—O—(R_(N-5)) ,

[0766] (32) —(CH₂)₀₋₄—O—(R_(N-5))—COOH,

[0767] (33) —(CH₂)₀₋₄—S—(R_(N-5)) ,

[0768] (34) —(CH₂)₀₋₄—O-(C₁-C₆ alkyl) wherein the alkyl group isoptionally substituted with one, two, three, four, or five substituentsindependently selected from the group consisting of F, Cl, Br, and I,

[0769] (35) —(CH₂)₀₋₄-(C₃-C₈ cycloalkyl)

[0770] (36) C₂-C₆ alkenyl optionally substituted with C₁-C₃ alkyl,halogen, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, or —NR_(1-a)R_(1-b),

[0771] (37) C₂-C₆ alkynyl optionally substituted with C₁-C₃ alkyl, —F,—Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, or —NR_(1-a)R_(1-b),and

[0772] (38) —(CH₂)₀₋₄—N(—H or R_(N-5))—SO₂—R_(N-2);

[0773]

[0774] (IV) —(CR_(C-x)R_(C-y))₀₋₄—R_(C-heteroaryl) whereinR_(C-heteroaryl) at each occurrence is independently selected from thegroup consisting of pyridinyl, pyrimidinyl, quinolinyl, benzothienyl,indolyl, indolinyl, pryidazinyl, pyrazinyl, isoindolyl, isoquinolyl,quinazolinyl, quinoxalinyl, phthalazinyl, imidazolyl, isoxazolyl,pyrazolyl, oxazolyl, thiazolyl, indolizinyl, indazolyl,benzoisothiazolyl, benzimidazolyl, benzofuranyl, furanyl, thienyl,pyrrolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl,oxazolopyridinyl, isothiazolyl, naphthyridinyl, cinnolinyl, carbazolyl,beta-carbolinyl, isochromanyl, chromanyl, tetrahydroisoquinolinyl,isoindolinyl, isobenzotetrahydrofuranyl, isobenzotetrahydrothienyl,isobenzothienyl, benzoxazolyl, pyridopyridinyl, benzotetrahydrofuranyl,benzotetrahydrothienyl, purinyl, benzodioxolyl, triazinyl, henoxazinyl,phenothiazinyl, pteridinyl, benzothiazolyl, imidazopyridinyl,imidazothiazolyl, dihydrobenzisoxazinyl, benzisoxazinyl, benzoxazinyl,dihydrobenzisothiazinyl, benzopyranyl, benzothiopyranyl, coumarinyl,isocoumarinyl, chromonyl, chromanonyl, tetrahydroquinolinyl,dihydroquinolinyl, dihydroquinolinonyl,dihydroisoquinolinonyl,dihydrocoumarinyl, dihydroisocoumarinyl,isoindolinonyl, benzodioxanyl, benzoxazolinonyl, imidazopyrazolyl,quinazolinonyl, pyrazopyridyl, benzooxadiazolyl, dihydropyrimidinonyl,dihydrobenzofuranonyl,

[0775] where the R_(C-heteroaryl) group is bonded by any atom of theparent R_(C-heteroaryl) group substituted by hydrogen such that the newbond to the R_(C-heteroaryl) group replaces the hydrogen atom and itsbond, where heteroaryl is optionally substituted 1, 2, 3, or 4 groupsthat are independently:

[0776] (1) C₁-C₆ alkyl, optionally substituted with 1, 2, or 3 groupsindependently selected from the group consisting of C₁-C₃ alkyl, —F,—Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b),

[0777] (2) —OH,

[0778] (3) —NO₂,

[0779] (4) —F, —Cl, —Br, —I,

[0780] (5) —CO—OH,

[0781] (6) —C≡N,

[0782] (V) C₂-C₁₀ alkenyl optionally substituted with one, two or threesubstituents independently selected from the group consisting of C₁-C₃alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁-C₆ alkoxy, —O-phenyl,and —NR_(1-a)R_(1-b),

[0783] (VI) C₂-C₁₀ alkynyl optionally substituted with one, two or threesubstituents independently selected from the group consisting of C₁-C₃alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁-C6 alkoxy, —O-phenyl,and —NR_(1-a)R_(1-b),

[0784] (VII) —(C₁-C₆ alkyl)-O-(C₁-C₆ alkyl)-OH,

[0785] (VIII) —CH₂—NH—CH₂—CH(—O—CH₂—CH₃)₂,

[0786] (IX) —(CH₂)₀₋₆—C(═NR_(1-a)) (NR_(1-a)R_(1-b));

[0787] where R_(N) is

[0788] (I) R_(N-1)—X_(N)— where X_(N) is —CO—, and where R_(N-1) isselected from the group consisting of:

[0789] (A) phenyl, which is optionally substituted with one, two orthree of the following substituents which can be the same or differentand are:

[0790] (1) C₁-C₆ alkyl, optionally substituted with one, two or threesubstituents selected from the group consisting of C₁-C₃ alkyl, —F, —Cl,—Br, —I, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b),

[0791] wherein R_(1-a) and R_(1-b) at each occurrence are independentlyH or C₁-C₆ alkyl,

[0792] (2) —OH,

[0793] (3) —NO₂,

[0794] (4) —F, —Cl, —Br, —I,

[0795] (5) —CO₂H,

[0796] (6) —C≡N,

[0797] (7) —(CH₂)₀₋₄—CO—NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) arethe same or different and are selected from the group consisting of:

[0798] (a) —H,

[0799] (b) —C₁-C₈ alkyl optionally substituted with one substituentselected from the group consisting of:

[0800] (i) —OH,

[0801] (ii) —NH₂,

[0802] (iii) phenyl,

[0803] (c) —C₁-C₈ alkyl optionally substituted with 1, 2, or 3 groupsthat are independently —F, —Cl, —Br, or —I,

[0804] (d) —C₃-C₈ cycloalkyl,

[0805] (e) —(C₁-C₂ alkyl)-(C₃-C₈ cycloalkyl),

[0806] (f) —(C₁-C₆ alkyl)-O-(C₁-C₃ alkyl)

[0807] (g) —C₂-C₆ alkenyl,

[0808] (h) —C₂-C₆ alkynyl,

[0809] (i) —C₁-C₆ alkyl chain with one double bond and one triple bond,

[0810] (j) —R_(1-aryl), wherein R_(1-aryl) at each occurrence isindependently phenyl, naphthyl, indanyl, indenyl, dihydronaphthyl, ortetralinyl each of which is optionally substituted with 1, 2, 3, or 4groups that are independently:

[0811] (i) C₁-C₆ alkyl optionally substituted with one, two or threesubstituents independently selected from the group consisting of C₁-C₃alkyl, —F, —Cl, —Br, —I, —OH, —SH, —NR_(1-a)R_(1-b), —C≡N, —CF₃, andC₁-C₃ alkoxy,

[0812] (ii) C₂-C₆ alkenyl with one or two double bonds, optionallysubstituted with one, two or three substituents independently selectedfrom the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃alkoxy, and —NR_(1-a)R_(1-b),

[0813] (iii) C₂-C₆ alkynyl optionally substituted with 1, 2, or 3 groupsthat are independently selected from the group consisting of —F, —Cl,—OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b),

[0814] (iv) —F, Cl, —Br and —I,

[0815] (v) —C₁-C₆ alkoxy optionally substituted with 1, 2, or 3 —F,

[0816] (vi) —NR_(N-2)R_(N-3),

[0817] (vii) —OH,

[0818] (viii) —C≡N,

[0819] (ix) C₃-C₇ cycloalkyl, optionally substituted with 1, 2, or 3groups that are selected from the group consisting of —F, —Cl, —OH, —SH,—C≡N, —CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b),

[0820] (x) —CO-(C₁-C₄ alkyl)

[0821] (xi) —SO₂—NR_(1-a)R_(1-b),

[0822] (xii) —CO—NR_(1-a)R_(1-b), or

[0823] (xiii) —SO₂-(C₁-C₄ alkyl)

[0824] (k) —R_(1-heteroaryl), wherein R_(1-heteroaryl) at eachoccurrence is independently selected from the group consisting ofpyridinyl, pyrimidinyl, quinolinyl, benzothienyl, indolyl, indolinyl,pryidazinyl, pyrazinyl, isoindolyl, isoquinolyl, quinazolinyl,quinoxalinyl, phthalazinyl, imidazolyl, isoxazolyl, pyrazolyl, oxazolyl,thiazolyl, indolizinyl, indazolyl, benzothiazolyl, benzimidazolyl,benzofuranyl, furanyl, thienyl, pyrrolyl, oxadiazolyl, thiadiazolyl,triazolyl, tetrazolyl, oxazolopyridinyl, imidazopyridinyl, isothiazolyl,naphthyridinyl, cinnolinyl, carbazolyl, beta-carbolinyl, isochromanyl,chromanyl, tetrahydroisoquinolinyl, isoindolinyl,isobenzotetrahydrofuranyl, isobenzotetrahydrothienyl, isobenzothienyl,benzoxazolyl, pyridopyridinyl, benzotetrahydrofuranyl,benzotetrahydrothienyl, purinyl, benzodioxolyl, triazinyl, phenoxazinyl,phenothiazinyl, pteridinyl, benzothiazolyl, imidazopyridinyl,imidazothiazolyl, dihydrobenzisoxazinyl, benzisoxazinyl, benzoxazinyl,dihydrobenzisothiazinyl, benzopyranyl, benzothiopyranyl, coumarinyl,isocoumarinyl, chromonyl, chromanonyl, pyridinyl-N-oxide,tetrahydroquinolinyl, dihydroquinolinyl, dihydroquinolinonyl,dihydroisoquinolinonyl, dihydrocoumarinyl, dihydroisocoumarinyl,isoindolinonyl, benzodioxanyl, benzoxazolinonyl, pyrrolyl N-oxide,pyrimidinyl N-oxide, pyridazinyl N-oxide, pyrazinyl N-oxide, quinolinylN-oxide, indolyl N-oxide, indolinyl N-oxide, isoquinolyl N-oxide,quinazolinyl N-oxide, quinoxalinyl N-oxide, phthalazinyl N-oxide,imidazolyl N-oxide, isoxazolyl N-oxide, oxazolyl N-oxide, thiazolylN-oxide, indolizinyl N-oxide, indazolyl N-oxide, benzothiazolyl N-oxide,benzimidazolyl N-oxide, pyrrolyl N-oxide, oxadiazolyl N-oxide,thiadiazolyl N-oxide, triazolyl N-oxide, tetrazolyl N-oxide,benzothiopyranyl S-oxide, and benzothiopyranyl S,S-dioxide,

[0825] where the R_(1-heteroaryl) group is optionally substituted with1, 2, 3, or 4 groups that are independently:

[0826] (i) C₁-C₆ alkyl optionally substituted with 1, 2, or 3 groupsindependently selected from the group consisting of C₁-C₃ alkyl, —F,—Cl, —Br, —I, —OH, —SH, —NR_(1-a)R_(1-b), —C≡N, —CF₃, and C₁-C₃ alkoxy,

[0827] (ii) C₂-C₆ alkenyl optionally substituted with 1, 2, or 3 groupsthat are independently —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, or—NR_(1-a)R_(1-b),

[0828] (iii) C₂-C₆ alkynyl optionally substituted with 1, 2, or 3 groupsthat are independently —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, or—NR_(1-a)R_(1-b),

[0829] (iv) —F, —Cl, —Br and —I,

[0830] (v) —C₁-C₆ alkoxy optionally substituted with one, two, or three—F,

[0831] (vi) —(CH₂)₀₋₄—NR_(N-2)R_(N-3),

[0832] (vii) —OH,

[0833] (viii) —C≡N,

[0834] (ix) (CH₂)₀₋₄-C₃-C₇ cycloalkyl, optionally substituted with 1, 2,or 3 groups that are independently selected from the group consisting of—F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b),

[0835] (x) (CH₂)₀₋₄—CO-(C₁-C₆ alkyl)

[0836] (xi) (CH₂)₀₋₄—SO₂—NR_(N-2)R_(N-3),

[0837] (xii) (CH₂)₀₋₄—CO—NR_(N-2)R_(N-3),

[0838] (xiii) (CH₂)₀₋₄—SO₂-(C₁-C₆ alkyl),

[0839] (xiv) (CH₂)₀₋₄—N(R_(N-2))—SO₂—, and

[0840] (xv) (CH₂)₀₋₄—N(R_(N-2))—C(O)—,

[0841] (1) —R_(1-heterocycle), wherein

[0842] R_(1-heterocycle) at each occurrence is independently selectedfrom the group consisting of morpholinyl, thiomorpholinyl,thiomorpholinyl S-oxide, thiomorpholinyl S,S-dioxide, piperazinyl,homopiperazinyl, pyrrolidinyl, pyrrolinyl, tetrahydropyranyl,piperidinyl, tetrahydrofuranyl, tetrahydrothienyl, homopiperidinyl,homomorpholinyl, homothiomorpholinyl, homothiomorpholinyl S,S-dioxide,oxazolidinonyl, dihydropyrazolyl, dihydropyrrolyl, dihydropyrazinyl,dihydropyridinyl, dihydropyrimidinyl, dihydrofuryl, dihydropyranyl,tetrahydrothienyl S-oxide, tetrahydrothienyl S,S-dioxide, andhomothiomorpholinyl S-oxide,

[0843] where the R_(1-heterocycle) group is bonded by any atom of theparent R_(1-heterocycle) group substituted by hydrogen such that the newbond to the R_(1-heterocycle) group replaces the hydrogen atom and itsbond, where heterocycle is optionally substituted with 1, 2, 3, or 4groups that are independently:

[0844] (a) C₁-C₆ alkyl optionally substituted with one, two or threesubstituents independently selected from the group consisting of C₁-C₃alkyl, halogen, —OH, —SH, —NR_(1-a)R_(1-b)—C≡N, —CF₃, and C₁-C₃ alkoxy,

[0845] (b) C₂-C₆ alkenyl with one or two double bonds, optionallysubstituted with one, two or three substituents independently selectedfrom the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃alkoxy, and —NR_(1-a)R_(1-b)

[0846] (c) C₂-C₆ alkynyl with one or two triple bonds, optionallysubstituted with one, two or three substituents independently selectedfrom the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃alkoxy, and —NR_(1-a)R_(1-b)

[0847] (d) halogen,

[0848] (e) C₁-C₆ alkoxy,

[0849] (f) —C₁-C₆ alkoxy optionally substituted with one, two, or three—F,

[0850] (g) —NR_(N-2)R_(N-3),

[0851] (h) —OH,

[0852] (i) —C≡N,

[0853] (j) (CH₂)₀₋₄-(C₃-C₈ cycloalkyl), optionally substituted with 1,2, or 3 groups independently selected from the group consisting of —F,—Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b),

[0854] (k) —(CH₂)₀₋₄—CO-(C₁-C₄ alkyl),

[0855] (l) —(CH₂)₀₋₄—SO₂—NR_(1-a)R_(1-b),

[0856] (m) —(CH₂)₀₋₄—CO—NR_(1-a)R_(1-b),

[0857] (n) —(CH₂)₀₋₄—SO₂-(C₁-C₆ alkyl), and

[0858] (o) ═O,

[0859] (p) —(CH₂)₀₋₄—N(R_(N-2))—SO₂—

[0860] (q) —(CH₂)₀₋₄—N(R_(N-2))—C(O)—

[0861] (8) —(CH₂)₀₋₄—CO-(C₁-C₁₂ alkyl),

[0862] (9) —(CH₂)₀₋₄—CO-(C₂-C₁₂ alkenyl)

[0863] (10) —(CH₂)₀₋₄—CO-(C₂-C₁₂ alkynyl)

[0864] (11) —(CH₂)₀₋₄—CO-(C₃-C₈ cycloalkyl),

[0865] (12) —(CH₂)₀₋₄—CO—R_(1-aryl),

[0866] (13) —(CH₂)₀₋₄—CO—R_(1-heteroaryl),

[0867] (14) —(CH₂)₀₋₄—CO—R_(1-heterocycle),

[0868] (15) —CH₂)₀₋₄—CO—R_(N-4) wherein R_(N-4) is selected from thegroup consisting of phenyl, morpholinyl, thiomorpholinyl, piperazinyl,piperidinyl, homomorpholinyl, homothiomorpholinyl, homothiomorpholinylS-oxide, homothiomorpholinyl S,S-dioxide, pyrrolinyl, thienyl,pyrazolyl, pyridyl N-oxide, oxazolyl, thiazolyl, imidazolyl, andpyrrolidinyl where each group is optionally substituted with one, two,three, or four groups that are independently C₁-C₆ alkyl,

[0869] (16) —(CH₂)₀₋₄—CO—O—R_(N-5) where R_(N-5) is selected from thegroup consisting of:

[0870] (a) C₁-C₆ alkyl,

[0871] (b) —(CH₂)₀₋₂—(R_(1-aryl))

[0872] (c) C₂-C₆ alkenyl,

[0873] (d) C₂-C₆ alkynyl,

[0874] (e) —(CH₂)₀₋₂-C₃-C₈ cycloalkyl,

[0875] (f) —(CH₂)₀₋₂—(R_(1-heteroaryl)) and

[0876] (g) —(CH₂)₀₋₂—(R_(1-heterocycle))

[0877] (17) —(CH₂)₀₋₄—SO₂—NR_(N-2)R_(N-3),

[0878] (18) —(CH₂)₀₋₄—SO-(C₁-C₈ alkyl)

[0879] (19) —(CH₂)₀₋₄—SO₂-(C₁-C₁₂ alkyl)

[0880] (20) —(CH₂)₀₋₄—SO₂-(C₃-C₈ cycloalkyl),

[0881] (21) —(CH₂)₀₋₄—N(H or R_(N-5))—CO—O—R_(N-5),

[0882] (22) —(CH₂)₀₋₄—N (H or R_(N-5))—CO—N(R_(N-5))₂,

[0883] (23) —(CH₂)₀₋₄—N—CS—N(R_(N-5))₂,

[0884] (24) —(CH₂)₀₋₄—N(H or R_(N-5))—CO—R_(N-2),

[0885] (25) —(CH₂)₀₋₄—NR_(N-2)R_(N-3),

[0886] (26) —(CH₂)₀₋₄—R_(N-4),

[0887] (27) —(CH₂)₀₋₄—O—CO-(C₁-C₆ alkyl)

[0888] (28) —(CH₂)₀₋₄—O—P(O)—(OR₁₀₀)₂ wherein

[0889] R₁₀₀ at each occurrence is independently —H or C₁-C₄ alkyl,

[0890] (29) —(CH₂)₀₋₄—O—CO—N(R_(N-5))₂,

[0891] (30) —(CH₂)₀₋₄—O—CS—N(R_(N-5))₂,

[0892] (31) —(CH₂)₀₋₄—O—(R_(N-5)),

[0893] (32) —(CH₂)₀₋₄—O—(R_(N-5))—COOH,

[0894] (33) —(CH₂)₀₋₄—S—(R_(N-5)) ,

[0895] (34) —(CH₂)₀₋₄—O-(C₁-C₆ alkyl optionally substituted with one,two, three, four, or five of —F),

[0896] (35) C₃-C₈ cycloalkyl,

[0897] (36) C₂-C₆ alkenyl optionally substituted with C₁-C₃ alkyl, —F,—Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, or —NR_(1-a)R_(1-b),

[0898] (37) C₂-C₆ alkynyl optionally substituted with C₁-C₃ alkyl, —F,—Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, or —NR_(1-a)R_(1-b),

[0899] (38) —(CH₂)₀₋₄—N(H or R_(N-5))—SO₂—R_(N-2),

[0900] (39) —(CH₂)₁₋₄-(C₃-C₈ cycloalkyl) ,

[0901] (B) —R_(N-heteroaryl) where R_(N-heteroaryl) is selected from thegroup consisting of pyridinyl, indolyl, indolinyl, isoindolyl,imidazolyl, isoxazolyl, oxazolyl, thiazolyl, indolizinyl andisochromanyl,

[0902] where the R_(N-heteroaryl) group is bonded by any atom of theparent R_(N-heteroaryl) group substituted by hydrogen such that the newbond to the R_(N-heteroaryl) group replaces the hydrogen atom and itsbond, where heteroaryl is optionally substituted with one, two, three,or four of:

[0903] (1) C₁-C₆ alkyl, optionally substituted with one, two or threesubstituents selected from the group consisting of C₁-C₃ alkyl, —F, —Cl,—Br, —I, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b),

[0904] (2) —OH,

[0905] (3) —NO₂,

[0906] (4) —F, —Cl, —Br, —I,

[0907] (5) —CO₂H,

[0908] (6) —C≡N,

[0909] (7) —(CH₂)₀₋₄—CO—NR_(N-2)R_(N-3),

[0910] (8) —(CH₂)₀₋₄—CO-(C₁-C₁₂ alkyl),

[0911] (9) —(CH₂)₀₋₄—CO-(C₂-C₁₂ alkenyl)

[0912] (10) —(CH₂)₀₋₄—CO-(C₂-C₁₂ alkynyl)

[0913] (11) —(CH₂)₀₋₄—CO-(C₃-C₈ cycloalkyl)

[0914] (12) —(CH₂)₀₋₄—CO—R_(1-aryl),

[0915] (13) —(CH₂)₀₋₄—CO—R_(1-heteroaryl),

[0916] (14) —(CH₂)₀₋₄—CO—R_(1-heterocycle),

[0917] (15) —CH₂)₀₋₄—CO—R_(N-4)

[0918] (16) —(CH₂)₀₋₄—CO—O—R_(N-5)

[0919] (17) —(CH₂)₀₋₄—SO₂—NR_(N-2)R_(N-3),

[0920] (18) —(CH₂)₀₋₄—SO-(C₁-C₈ alkyl),

[0921] (19) —(CH₂)₀₋₄—SO₂-(C₁-C₁₂ alkyl)

[0922] (20) —(CH₂)₀₋₄—SO₂-(C₃-C₈ cycloalkyl),

[0923] (21) —(CH₂)₀₋₄—N(H or R_(N-5) )—CO—O—R_(N-5),

[0924] (22) —(CH₂)₀₋₄—N(H or R_(N-5))—CO—N(R_(N-5))₂, ,

[0925] (23) —(CH₂)₀₋₄—N—CS—N(R_(N-5))₂,

[0926] (24) —(CH₂)₀₋₄—N(—H or R_(N-5))—CO—R_(N-2),

[0927] (25) —(CH₂)₀₋₄—NR_(N-2)R_(N-3),

[0928] (26) —(CH₂)₀₋₄—R_(N-4),

[0929] (27) —(CH₂)₀₋₄—O—CO-(C₁-C₆ alkyl)

[0930] (28) —(CH₂)₀₋₄—O—P(O)—(OR₁₀₀)₂,

[0931] (29) —(CH₂)₀₋₄—O—CO—N(R_(N-5))₂,

[0932] (30) —(CH₂)₀₋₄—O—CS—N(R_(N-5))₂,

[0933] (31) —(CH₂)₀₋₄—O—(R_(N-5)),

[0934] (32) —(CH₂)₀₋₄—O—(R_(N-5))—COOH,

[0935] (33) —(CH₂)₀₋₄—S—(R_(N-5))

[0936] (34) —(CH₂)₀₋₄—O-(C₁-C₆ alkyl optionally substituted with one,two, three, four, or five of —F),

[0937] (35) C₃-C₈ cycloalkyl,

[0938] (36) C₂-C₆ alkenyl optionally substituted with C₁-C₃ alkyl, —F,—Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, or

[0939] —NR_(1-a)R_(1-b),

[0940] (37) C₂-C₆ alkynyl optionally substituted with C₁-C₃ alkyl, —F,—Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, or —NR_(1-a)R_(1-b),

[0941] (38) —(CH₂)₀₋₄—N(—H or R_(N-5))—SO₂—R_(N-2),

[0942] (39) —(CH₂)₁₋₄-C₃-C₈ cycloalkyl,

[0943] (C) R_(N-aryl)—W—R_(N-aryl),

[0944] (D) R_(N-aryl)—W—R_(N-heteroaryl),

[0945] (E) R_(N-aryl)—W—R_(1-heterocycle),

[0946] (F) R_(N-heteroaryl)—W—R_(N-aryl),

[0947] (G) R_(N-heteroaryl)—W—R_(N-heteroaryl),

[0948] (H) R_(N-heteroaryl)—W—R_(N-1-heterocycle),

[0949] (I) R_(N-heterocycle)—W—R_(N-aryl),

[0950] (J) R_(N-heterocycle)—W—R_(N-heteroaryl),

[0951] (K) R_(N-heterocycle)—W—R_(N-1-heterocycle),

[0952] where W is

[0953] (7) —(CH₂)₁₋₄—,

[0954] (8) —O—,

[0955] (9) —S(O)₀₋₂—,

[0956] (10) —N(R_(N-5))—,

[0957] (11) —CO—; or

[0958] (12) a bond;

[0959]

[0960] (II) —CO—(C₁-C₆ alkyl)-M-(C₁-C₆ alkyl), where M is S, SO or SO₂,and wherein each alkyl is unsubstituted or substituted with one, two, orthree of substituents independently selected from the group consistingof:

[0961] (A) —NH—CO-(C₁-C₆ alkyl),

[0962] (B) —NH—CO—O—R_(N-8),

[0963] (C) —NR_(N-2)R_(N-3);

[0964] where R₁ is

[0965] —(CH₂)_(n1)-phenyl, where n₁ is zero or one, and which isoptionally substituted with one, two, three or four of the followingsubstituents on the phenyl ring:

[0966] (A) C₁-C₆ alkyl optionally substituted with one, two or threesubstituents selected from the group consisting of C₁-C₃ alkyl, —F, —Cl,—Br, —I, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b),

[0967] (B) C₂-C₆ alkenyl with one or two double bonds, optionallysubstituted with one, two or three substituents selected from the groupconsisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and—NR_(1-a)R_(1-b),

[0968] (C) C₂-C₆ alkynyl with one or two triple bonds, optionallysubstituted with one, two or three substituents selected from the groupconsisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and—NR_(1-a)R_(1-b),

[0969] (D) —F, Cl, —Br or —I,

[0970] (F) —C₁-C₆ alkoxy optionally substituted with one, two or threeof —F,

[0971] (G) —NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) are as definedbelow,

[0972] (H) —OH,

[0973] (I) —C≡N,

[0974] (J) C₃-C₇ cycloalkyl, optionally substituted with one, two orthree substituents selected from the group consisting of —F, —Cl, —OH,—SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b),

[0975] (K) —CO-(C₁-C₄ alkyl),

[0976] (L) —SO₂—NR_(1-a)R_(1-b),

[0977] (M) —CO—NR_(1-a)R_(1-b),

[0978] (N) —SO₂-(C₁-C₄ alkyl); and

[0979] where R₂ is

[0980] (I) —(Z)-C₁-C₆ alkyl, where Z is a bond, —C(O), —CO₂— or —SO₂—,wherein the alkyl group is optionally substituted with one, two or threesubstituents selected from the group consisting of C₁-C₃ alkyl, C₁-C₇alkyl (optionally substituted with C₁-C₃ alkyl and C₁-C₃ alkoxy), —F,—Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, —NR_(1-a)R_(1-b) whereR_(1-a) and R_(1-b) are independently —H or C₁-C₆ alkyl, and —OC═ONR_(1-a)R_(1-b),

[0981] (II) —(Z)—CH₂—S(O)₀₋₂-(C₁-C₆ alkyl),

[0982] (III) —(Z)—CH₂—CH₂—S(O)₀₋₂-(C₁-C₆ alkyl)

[0983] (IV) —(Z)-C₂-C₆ alkenyl with one or two double bonds, optionallysubstituted with one, two or three substituents selected from the groupconsisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and—NR_(1-a)R_(1-b),

[0984] (V) —(Z)-C₂-C₆ alkynyl with one or two triple bonds, optionallysubstituted with one, two or three substituents selected from the groupconsisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and—NR_(1-a)R_(1-b),

[0985] (VI) —(Z)—(CH₂)_(n1)—(R_(1-aryl)), where Z is a bond, CO, CO₂ orSO₂, where n, is zero or one and where R_(1-aryl) is phenyl, 1-naphthyl,2-naphthyl and indanyl, indenyl, dihydronaphthalyl, or tetralinyloptionally substituted with one, two, three or four of the followingsubstituents on the aryl ring:

[0986] (A) C₁-C₆ alkyl optionally substituted with one, two or threesubstituents selected from the group consisting of C₁-C₃ alkyl, —F, —Cl,—Br, —I, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b),

[0987] (B) C₂-C₆ alkenyl with one or two double bonds, optionallysubstituted with one, two or three substituents selected from the groupconsisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and—NR_(1-a)R_(1-b),

[0988] (C) C₂-C₆ alkynyl with one or two triple bonds, optionallysubstituted with one, two or three substituents selected from the groupconsisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and—NR_(1-a)R_(1-b),

[0989] (D) —F, Cl, —Br or —I,

[0990] (F) —C₁-C₆ alkoxy optionally substituted with one, two or threeof —F,

[0991] (G) —NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) are as definedbelow,

[0992] (H) —OH,

[0993] (I) —C≡N,

[0994] (J) C₃-C₇ cycloalkyl, optionally substituted with one, two orthree substituents selected from the group consisting of —F, —Cl, —OH,—SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b),

[0995] (K) —CO-(C₁-C₄ alkyl),

[0996] (L) —SO₂—NR_(1-a)R_(1-b),

[0997] (M) —CO—NR_(1-a)R_(1-b),

[0998] (N) —SO₂-(C₁-C₄ alkyl)

[0999] (VII) —(Z)—(CH₂)_(n1)—(R_(1-heteroaryl)) where n₁ is as definedabove and where R_(1-heteroaryl) is selected from the group consistingof:

[1000] pyridinyl, pyrimidinyl, quinolinyl, benzothienyl, indolyl,indolinyl, pryidazinyl, pyrazinyl, isoindolyl, isoquinolyl,quinazolinyl, quinoxalinyl, phthalazinyl, imidazolyl, isoxazolyl,pyrazolyl, oxazolyl, thiazolyl, indolizinyl, indazolyl, benzothiazolyl,benzimidazolyl, benzofuranyl, furanyl, thienyl, pyrrolyl, oxadiazolyl,thiadiazolyl, triazolyl, tetrazolyl, oxazolopyridinyl, imidazopyridinyl,isothiazolyl, naphthyridinyl, cinnolinyl, carbazolyl, beta-carbolinyl,isochromanyl, chromanyl, tetrahydroisoquinolinyl, isoindolinyl,isobenzotetrahydrofuranyl, isobenzotetrahydrothienyl, isobenzothienyl,benzoxazolyl, pyridopyridinyl, benzotetrahydrofuranyl,benzotetrahydrothienyl, purinyl, benzodioxolyl, triazinyl, phenoxazinyl,phenothiazinyl, pteridinyl, benzothiazolyl, imidazopyridinyl,imidazothiazolyl, dihydrobenzisoxazinyl, benzisoxazinyl, benzoxazinyl,dihydrobenzisothiazinyl, benzopyranyl, benzothiopyranyl, coumarinyl,isocoumarinyl, chromonyl, chromanonyl, pyridinyl-N-oxide,tetrahydroquinolinyl, dihydroquinolinyl, dihydroquinolinonyl,dihydroisoquinolinonyl, dihydrocoumarinyl, dihydroisocoumarinyl,isoindolinonyl, benzodioxanyl, benzoxazolinonyl, pyrrolyl N-oxide,pyrimidinyl N-oxide, pyridazinyl N-oxide, pyrazinyl N-oxide, quinolinylN-oxide, indolyl N-oxide, indolinyl N-oxide, isoquinolyl N-oxide,quinazolinyl N-oxide, quinoxalinyl N-oxide, phthalazinyl N-oxide,imidazolyl N-oxide, isoxazolyl N-oxide, oxazolyl N-oxide, thiazolylN-oxide, indolizinyl N-oxide, indazolyl N-oxide, benzothiazolyl N-oxide,benzimidazolyl N-oxide, pyrrolyl N-oxide, oxadiazolyl N-oxide,thiadiazolyl N-oxide, triazolyl N-oxide, tetrazolyl N-oxide,benzothiopyranyl S-oxide, benzothiopyranyl S,S-dioxide,

[1001] where the R_(1-heteroaryl) group is bonded to —(CH₂)_(n1)— by anyring atom of the parent R_(N-heteroaryl) group substituted by hydrogensuch that the new bond to the R_(1-heteroaryl) group replaces thehydrogen atom and its bond, where heteroaryl is optionally substitutedwith one, two, three or four of:

[1002] (1) C₁-C₆ alkyl optionally substituted with one, two or threesubstituents selected from the group consisting of C₁-C₃ alkyl, —F, —Cl,—Br, —I, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b),

[1003] (2) C₂-C₆ alkenyl with one or two double bonds, optionallysubstituted with one, two or three substituents selected from the groupconsisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and—NR_(1-a)R_(1-b),

[1004] (3) C₂-C₆ alkynyl with one or two triple bonds, optionallysubstituted with one, two or three substituents selected from the groupconsisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and—NR_(1-a)R_(1-b),

[1005] (4) —F, Cl, —Br or —I,

[1006] (6) —C₁-C₆ alkoxy optionally substituted with one, two, or threeof —F,

[1007] (7) —NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) are as definedbelow,

[1008] (8) —OH,

[1009] (9) —C≡N,

[1010] (10) C₃-C₇ cycloalkyl, optionally substituted with one, two orthree substituents selected from the group consisting of —F, —Cl, —OH,—SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b),

[1011] (11) —CO-(C₁-C₄ alkyl)

[1012] (12) —SO₂—NR_(1-a)R_(1-b),

[1013] (13) —CO—NR_(1-a)R_(1-b), or

[1014] (14) —SO₂-(C₁-C₄ alkyl), with the proviso that when n₁ is zeroR_(1-heteroaryl) is not bonded to the carbon chain by nitrogen, or

[1015] (VIII) —(Z) —(CH₂)_(n1)—(R_(1-heterocycle)) where n₁ is asdefined above and R_(1-heterocycle) is selected from the groupconsisting of:

[1016] morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide,thiomorpholinyl S,S-dioxide, piperazinyl, homopiperazinyl, pyrrolidinyl,pyrrolinyl, tetrahydropyranyl, piperidinyl, tetrahydrofuranyl,tetrahydrothienyl, homopiperidinyl, homomorpholinyl, homomorpholinylS-oxide, homothiomorpholinyl S,S-dioxide, oxazolidinonyl,dihydropyrazolyl, dihydropyrrolyl dihydropyrazinyl dihydropyridinyldihydropyrimidinyl, dihydrofuryl, dihydropyranyl, tetrahydrothienylS-oxide, tetrahydrothienyl S,S-dioxide, homothiomorpholinyl S-oxide,

[1017] where the R_(1-heterocycle) group is bonded by any atom of theparent R_(1-heterocycle) group substituted by hydrogen such that the newbond to the R_(1-heterocycle) group replaces the hydrogen atom and itsbond, where heterocycle is optionally substituted with one, two, threeor four:

[1018] (1) C₁-C₆ alkyl optionally substituted with one, two or threesubstituents selected from the group consisting of C₁-C₃ alkyl, —F, —Cl,—Br, —I, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b),

[1019] (2) C₂-C₆ alkenyl with one or two double bonds, optionallysubstituted with one, two or three substituents selected from the groupconsisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and—NR_(1-a)R_(1-b),

[1020] (3) C₂-C₆ alkynyl with one or two triple bonds, optionallysubstituted with one, two or three substituents selected from the groupconsisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and—NR_(1-a)R_(1-b),

[1021] (4) —F, Cl, —Br, or —I,

[1022] (5) C₁-C₆ alkoxy,

[1023] (6) —C₁-C₆ alkoxy optionally substituted with one, two, or three—F,

[1024] (7) —NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) are as definedbelow,

[1025] (8) —OH,

[1026] (9) —C≡N,

[1027] (10) C₃-C₇ cycloalkyl, optionally substituted with one, two orthree substituents selected from the group consisting of —F, —Cl, —OH,—SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b),

[1028] (11) —CO-(C₁-C₄ alkyl)

[1029] (12) —SO₂—NR_(1-a)R_(1-b),

[1030] (13) —CO—NR_(1-a)R_(1-b),

[1031] (14) —SO₂-(C₁-C₄ alkyl)

[1032] (15) ═O, with the proviso that when n₁ is zero R_(1-heterocycle)is not bonded to the carbon chain by nitrogen; and

[1033] where R₂₀ is H or C₁₆ alkyl or alkenyl.

[1034] In another preferred embodiment relative to formula II, Rc is—(CR_(c-x)R_(c-y))₀₋₄—R_(c-aryl) where R_(c-x) and R_(c-y) areindependently selected from the group consisting of

[1035] —H,

[1036] C₁-C₄ alkyl optionally substituted with 1 or 2 —OH,

[1037] C₁-C₄ alkoxy optionally substituted with 1, 2, or 3 halogen,

[1038] —(CH₂)₀₋₄-C₃-C₈ cycloalkyl,

[1039] C₂-C₆ alkenyl containing one or two double bonds,

[1040] C₂-C₆ alkynyl containing one or two triple bonds, and phenyl,

[1041] or

[1042] R_(c-x) and R_(c-y) are taken together with the carbon to whichthey are attached to form a carbocycle of three, four, five, six orseven carbon atoms, where one carbon atom is optionally replaced by agroup selected from —O—, —S—, —SO₂—, —NR_(N-2)— and R_(c-aryl), wherein

[1043] R_(c-aryl) is phenyl, which is optionally substituted with 1, 2,or 3 groups that are independently:

[1044] (1) C₁-C₆ alkyl, optionally substituted with one, two or threesubstituents selected from the group consisting of C₁-C₃ alkyl, halogen,—OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b),

[1045] (2) —OH,

[1046] (3) —NO₂,

[1047] (4) halogen,

[1048] (5) —CO₂H,

[1049] (6) —C≡N.

[1050] In yet another preferred embodiment, Rc is—(CR_(c-x)R_(c-y))₀₋₄—R_(c-aryl) where R_(c-x) and R_(c-y) areindependently selected from the group consisting of

[1051] —H,

[1052] C₁-C₄ alkyl optionally substituted with 1 or 2 —OH,

[1053] C₁-C₄ alkoxy optionally substituted with 1, 2, or 3 halogen,

[1054] —(CH₂)₀₋₄-C₃-C₈ cycloalkyl,

[1055] C₂-C₆ alkenyl containing one or two double bonds,

[1056] C₂-C₆ alkynyl containing one or two triple bonds, and

[1057] phenyl,

[1058] or

[1059] R_(c-x) and R_(c-y) are taken together with the carbon to whichthey are attached to form a carbocycle of three, four, five, six orseven carbon atoms, where one carbon atom is optionally replaced by agroup selected from —O—, —S—, —SO₂—, —NR_(N-2)— and R_(c-aryl), wherein

[1060] —(CR_(c-x)R_(c-y))₀₋₄—R_(C-heteroaryl) is selected from the groupconsisting of pyridinyl, indolyl, indolinyl, isoindolyl, imidazolyl,isoxazolyl, oxazolyl, thiazolyl, indolizinyl and isochromanyl.

[1061] In another preferred embodiment relative to formula II, R_(C) isthe optionally substituted —C1-C10 alkyl groups as described above.

[1062] Preferred compounds of the formula II include, amongst others:

[1063] In another preferred embodiment, the invention provides compoundsof formula III:

[1064] or a pharmaceutically acceptable salt thereof wherein

[1065] R₁ represents phenyl (C₁-C₆)alkyl where the phenyl is optionallysubstituted with up to three groups independently selected from halogen,hydroxy, C₁-C₂ alkyl, C₁-C₂ alkoxy, amino, nitro, trifluoromethyl,cyano, mono(C₁-C₂)alkylamino and di(C₁-C₂) alkylamino;

[1066] R_(a) and R_(b) independently represent hydrogen, hydroxy, C₁-C₆alkyl, C₁-C₆ alkoxy, C₃-C₇ cycloalkyl, C₃-C₇ cycloalkyl(C₁-C₆)alkyl,C₃-C₇ cycloalkyl(C₁-C₆)alkoxy, halogen, cyano, amino,mono(C₁-C₆)alkylamino, di(C₁-C₆)alkylamino, mono- ordi(C₁-C₆)alkylaminosulfonyl, C₁-C₆ alkyl sulfonylamino, C₂-C₆ alkenyl,C₂-C₆ alkynyl, trifluoromethyl, mono(C₁-C₆)alkylaminocarbonyl, ordi(C₁-C₆)alkylaminocarbonyl and provided that not both R_(a) and R_(b)are hydrogen simultaneously;

[1067] R_(c) represents hydrogen, or C₁-C₆ alkyl, C₂-C₆ alkenyl, orC₂-C₆ alkynyl each of which is optionally substituted with halogen,hydroxy, amino, cyano, or trifluoromethyl;

[1068] R_(d) represents

[1069] phenyl optionally substituted with hydroxy, C₁-C₆ alkyl, C₁-C₆alkoxy, C₃-C₇ cycloalkyl, C₃-C₇ cycloalkyl(C₁-C₆)alkyl, C₃-C₇cycloalkyl(C₁-C₆)alkoxy, halogen, cyano, amino, mono(C₁-C₆)alkylamino,di(C₁-C₆)alkylamino, mono- or di(C₁-C₆)alkylaminosulfonyl, C₁-C₆ alkylsulfonylamino, C₂-C₆ alkenyl, C₂-C₆ alkynyl; or

[1070] C₁-C₆ alkyl optionally substituted with hydroxy, C₁-C₆ alkyl,C₁-C₆ alkoxy, halogen, cyano, amino, mono(C₁-C₆)alkylamino,di(C₁-C₆)alkylamino, C₂-C₆ alkenyl, C₂-C₆ alkynyl, or trifluoromethyl;and

[1071] R₂₀ represents hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, or trifluoromethyl.

[1072] In accordance witht this preferred embodiment, R₁ is benzyl wherethe phenyl is optionally substituted. Also preferably, the phenyl issubstituted with one or two groups independently selected from halogen,hydroxy, C₁-C₃ alkyl, amino, and trifluoromethyl. In another preferredembodiment, phenyl is substituted with two groups independently selectedfrom halogen, hydroxy, and trifluoromethyl. In an alternavie preferredembodiment, phenyl is disubstituted with halogen. Also preferably, R₁ is3,5-difluorobenzyl. Preferably, R_(a) and R_(b) are different and R_(b)represents mono- or di(C₁-C₆)alkylaminocarbonyl. Also preferably, R_(d)is phenyl optionally substituted with C₁-C₃ alkyl, C₁-C₃ alkoxy, amino,hydroxy, or halogen. In a further preferred embodiment, R_(c) ishydrogen or C₁-C₄ alkyl. Also preferably, R_(c) is C₁-C₃ alkyl. In yetanother preferred embodiment, R_(d) is C₁-C₆ lower alkyl and R₂₀ ishydrogen.

[1073] In another preferred embodiment, the invention provides forcompounds of formula IV:

[1074] where R_(a), R_(b), R₁ R_(c), R₂₀ and R_(d) are defined above forthis preferred embodiment. In another preferred embodiment, R₁ is benzylwhere the phenyl is disubstituted with chloro or fluoro; R_(c) is C₁-C₃alkyl; R_(d) is C₁-C₆ lower alkyl; R₂₀ is hydrogen or C₁-C₆ alkyl; andR_(b) is di(C₁-C₆)alkylaminocarbonyl attached to the 3-position of thephenyl group.

[1075] In another preferred embodiment, the invention provides compoundsof the formula V:

[1076] or a pharmaceutically acceptable salt thereof wherein

[1077] R₁ represents phenyl (C₁-C₆)alkyl where the phenyl is optionallysubstituted with up to three groups independently selected from halogen,hydroxy, C₁-C₂ alkyl, C₁-C₂ alkoxy, amino, nitro, trifluoromethyl,cyano, mono(C₁-C₂)alkylamino and di(C₁-C₂) alkylamino;

[1078] R_(a) and R_(b) independently represent hydrogen, hydroxy, C₁-C₆alkyl, C₁-C₆ alkoxy, C₃-C₇ cycloalkyl, C₃-C₇ cycloalkyl(C₁-C₆)alkyl,C₃-C₇ cycloalkyl (C₁-C₆) alkoxy, halogen, cyano, amino,mono(C₁-C₆)alkylamino, di(C₁-C₆)alkylamino, mono- or di(C₁-C₆)alkylaminosulfonyl, C₁-C₆ alkyl sulfonylamino, C₂-C₆ alkenyl,C₂-C₆ alkynyl, trifluoromethyl, mono(C₁-C₆)alkylaminocarbonyl, ordi(C₁-C₆) alkylaminocarbonyl and provided that not both R_(a) and R_(b)are hydrogen simultaneously;

[1079] R_(c) represents hydrogen, or C₁-C₆ alkyl, C₂-C₆ alkenyl, orC₂-C₆ alkynyl each of which is optionally substituted with halogen,hydroxy, amino, cyano, or trifluoromethyl;

[1080] R_(d) represents

[1081] phenyl optionally substituted with hydroxy, C₁-C₆ alkyl, C₁-C₆alkoxy, C₃-C₇ cycloalkyl, C₃-C₇ cycloalkyl(C₁-C₆)alkyl, C₃-C₇cycloalkyl(C₁-C₆)alkoxy, halogen, cyano, amino, mono(C₁-C₆)alkylamino,di(C₁-C₆)alkylamino, mono- or di(C₁-C₆)alkylaminosulfonyl, C₁-C₆ alkylsulfonylamino, C₂-C₆ alkenyl, C₂-C₆ alkynyl; or

[1082] C₁-C₆ alkyl optionally substituted with hydroxy, C₁-C₆ alkyl,C₁-C₆ alkoxy, halogen, cyano, amino, mono(C₁-C₆)alkylamino,di(C₁-C₆)alkylamino, C₂-C₆ alkenyl, C₂-C₆ alkynyl, or trifluoromethyl;and

[1083] R₂₀ represents hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, or trifluoromethyl.

[1084] In accordance with this preferred embodiment, R₁ is benzyl wherethe phenyl is optionally substituted. Preferably, the phenyl issubstituted with one or two groups independently selected from halogen,hydroxy, C₁-C₃ alkyl, amino, and trifluoromethyl. Also preferably,phenyl is substituted with two groups independently selected fromhalogen, hydroxy, and trifluoromethyl. Also preferably, phenyl isdisubstituted with halogen. In another preferred embodiment, R₁ is3,5-difluorobenzyl. Also preferably, R_(a) and R_(b) are different andR_(b) represents C₁-C₆)alkylsulfonylamino. Preferably, R_(d) is phenyloptionally substituted with C₁-C₃ alkyl, C₁-C₃ alkoxy, amino, hydroxy,or halogen. Preferably, R_(C) is hydrogen or C₁-C₄ alkyl. Preferably,R_(C) is C₁-C₃ alkyl. Also preferably, R_(d) is C₁-C₆ lower alkyl andR₂₀ is hydrogen. Further in accordance with this preferred embodiement,the invention provides compounds of the formula VI:

[1085] where R_(a), R_(b), R₁ R_(c) R₂₀ and R_(d) are defined above forthis preferred embodiment. In another preferred embodiment, R₁ is benzylwhere the phenyl is disubstituted with chloro or fluoro; R_(c) is C₁-C₃alkyl; R_(d) is C₁-C₆ lower alkyl; R₂₀ is hydrogen or C₁-C₆ alkyl; andR_(b) is alkylsulfonylamino attached to the 2-position of the thiazolylgroup.

[1086] Preferred compounds of the invention include:

[1087] In another embodiment, the invention provides a method oftreating a patient who has, or in preventing a patient from getting, adisease or condition selected from the group consisting of Alzheimer'sdisease, for helping prevent or delay the onset of Alzheimer's disease,for treating patients with mild cognitive impairment (MCI) andpreventing or delaying the onset of Alzheimer's disease in those whowould progress from MCI to AD, for treating Down's syndrome, fortreating humans who have Hereditary Cerebral Hemorrhage with Amyloidosisof the Dutch-Type, for treating cerebral amyloid angiopathy andpreventing its potential consequences, i.e. single and recurrent lobarhemorrhages, for treating other degenerative dementias, includingdementias of mixed vascular and degenerative origin, dementia associatedwith Parkinson's disease, dementia associated with progressivesupranuclear palsy, dementia associated with cortical basaldegeneration, diffuse Lewy body type of Alzheimer's disease and who isin need of such treatment which comprises administration of atherapeutically effective amount of a compound selected from the groupconsisting of an aza hydroxylated ethyl amine of the formula II:

[1088] or a pharmaceutically acceptable salt thereof, where Rc is

[1089] (I) —C₁-C₁₀ alkyl optionally substituted with one, two or threegroups independently selected from the group consisting of C₁-C₃ alkyl,halogen, —OH, —SH, —C≡N, —CF₃, C₁-C₆ alkoxy, —O-phenyl,—NR_(1-a)R_(1-b), —OC═O NR_(1-a)R_(1-b), —S(═O)₀₋₂ R_(1-a), —NR_(1-a)C═ONR_(1-a)R_(1-b), —C═O NR_(1-a)R_(1-b), and —S(═O)₂ NR_(1-a)R_(1-b)wherein

[1090] R_(1-a) and R_(1-b) at each occurrence are independently H orC₁-C₆ alkyl,

[1091] (II) —(CH₂)₀₋₃—(C₃-C₈) cycloalkyl where cycloalkyl can beoptionally substituted with one, two or three substituents independentlyselected from the group consisting of C₁-C₃ alkyl, halogen, —OH, —SH,—C—N, —CF₃, C₁-C₆ alkoxy, —O-phenyl, —CO₂H, —CO₂-(C₁-C₄ alkyl), and—NR_(1-a)R_(1-b)

[1092] (III) —(CR_(C-x)R_(C-y))₀₋₄—R_(C-aryl) where R_(C-x) and R_(C-y)are independently selected from the group consisting of

[1093] —H,

[1094] C₁-C₄ alkyl optionally substituted with 1 or 2 —OH,

[1095] C₁-C₄ alkoxy optionally substituted with 1, 2, or 3 halogen,

[1096] —(CH₂)₀₋₄—C₃-C₈ cycloalkyl,

[1097] C₂-C₆ alkenyl containing one or two double bonds,

[1098] C₂-C₆ alkynyl containing one or two triple bonds, and phenyl,

[1099] or

[1100] R_(C-x) and R_(C-y) are taken together with the carbon to whichthey are attached to form a carbocycle of three, four, five, six orseven carbon atoms, where one carbon atom is optionally replaced by agroup selected from —O—, —S—, —SO₂—, —NR_(N-2)— and R_(C-aryl), wherein

[1101] R_(C-aryl) is phenyl, which is optionally substituted with 1, 2,or 3 groups that are independently:

[1102] (1) C₁-C₆ alkyl, optionally substituted with one, two or threesubstituents selected from the group consisting of C₁-C₃ alkyl, halogen,—OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b),

[1103] (2) —OH,

[1104] (3) —NO₂,

[1105] (4) halogen,

[1106] (5) —CO₂H,

[1107] (6) —C—N,

[1108] (7) —(CH₂)₀₋₄—CO—NR_(N-2)R_(N-3) where

[1109] R_(N-2) and R_(N-3) are independently selected from the groupconsisting of:

[1110] (a) —H,

[1111] (b) —C₁-C₆ alkyl optionally substituted with one substituentselected from the group consisting of:

[1112] (i) —OH, and

[1113] (ii) —NH₂,

[1114] (c) —C₁-C₆ alkyl optionally substituted with 1, 2, or 3 groupsthat are independently —F, —Cl, —Br, —I, or OH,

[1115] (d) —C₃-C₇ cycloalkyl,

[1116] (e) —(C₁-C₂ alkyl)-(C₃-C₇ cycloalkyl),

[1117] (f) —(C₁-C₆ alkyl)-O-(C₁-C₃ alkyl)

[1118] (g) —C₂-C₆ alkenyl

[1119] (h) —C₂-C₆ alkynyl

[1120] (i) —C₁-C₆ alkyl chain with one double bond and one triple bond,

[1121] (j) —R_(1-aryl) wherein R_(1-aryl) at each occurrence isindependently phenyl, naphthyl, indanyl, indenyl, dihydronaphthyl, ortetralinyl each of which is optionally substituted with 1, 2, 3, or 4groups that are independently:

[1122] (i) C₁-C₆ alkyl optionally substituted with one, two or threesubstituents independently selected from the group consisting of C₁-C₃alkyl, —F, —Cl, —Br, —I, —OH, —SH, —NR_(1-a)R_(1-b), —C≡N, —CF₃, andC₁-C₃ alkoxy,

[1123] (ii) C₂-C₆ alkenyl with one or two double bonds, optionallysubstituted with one, two or three substituents independently selectedfrom the group consisting of —F, —Cl, —OH, —SH, —C—N, —CF₃, C₁-C₃alkoxy, and —NR_(1-a)R_(1-b),

[1124] (iii) C₂-C₆ alkynyl optionally substituted with 1, 2, or 3 groupsthat are independently selected from the group consisting of —F, —Cl,—OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b),

[1125] (iv) —F, Cl, —Br and —I,

[1126] (v) —C₁-C₆ alkoxy optionally substituted with 1, 2, or 3 —F,

[1127] (vi) —NR_(N-2)R_(N-3),

[1128] (vii) —OH,

[1129] (viii) —C≡N,

[1130] (ix) C₃-C₇ cycloalkyl, optionally substituted with 1, 2, or 3groups that are selected from the group consisting of —F, —Cl, —OH, —SH,—C—N, —CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b),

[1131] (x) —CO-(C₁-C₄ alkyl),

[1132] (xi) —SO₂—NR_(1-a)R_(1-b),

[1133] (xii) —CO—NR_(1-a)R_(1-b), or

[1134] (xiii) —SO₂-(C₁-C₄ alkyl)

[1135] (k) —R_(1-heteroaryl) wherein R_(1-heteroaryl) at each occurrenceis independently selected from the group consisting of pyridinyl,pyrimidinyl, quinolinyl, benzothienyl, indolyl, indolinyl, pryidazinyl,pyrazinyl, isoindolyl, isoquinolyl, quinazolinyl, quinoxalinyl,phthalazinyl, imidazolyl, isoxazolyl, pyrazolyl, oxazolyl, thiazolyl,indolizinyl, indazolyl, benzothiazolyl, benzimidazolyl, benzofuranyl,furanyl, thienyl, pyrrolyl, oxadiazolyl, thiadiazolyl, triazolyl,tetrazolyl, oxazolopyridinyl, imidazopyridinyl, isothiazolyl,naphthyridinyl, cinnolinyl, carbazolyl, beta-carbolinyl, isochromanyl,chromanyl, tetrahydroisoquinolinyl, isoindolinyl,isobenzotetrahydrofuranyl, isobenzotetrahydrothienyl, isobenzothienyl,benzoxazolyl, pyridopyridinyl, benzotetrahydrofuranyl,benzotetrahydrothienyl, purinyl, benzodioxolyl, triazinyl, phenoxazinyl,phenothiazinyl, pteridinyl, benzothiazolyl, imidazopyridinyl,imidazothiazolyl, dihydrobenzisoxazinyl, benzisoxazinyl, benzoxazinyl,dihydrobenzisothiazinyl, benzopyranyl, benzothiopyranyl, coumarinyl,isocoumarinyl, chromonyl, chromanonyl, pyridinyl-N-oxide,tetrahydroquinolinyl, dihydroquinolinyl, dihydroquinolinonyl,dihydroisoquinolinonyl, dihydrocoumarinyl, dihydroisocoumarinyl,isoindolinonyl, benzodioxanyl, benzoxazolinonyl, pyrrolyl N-oxide,pyrimidinyl N-oxide, pyridazinyl N-oxide, pyrazinyl N-oxide, quinolinylN-oxide, indolyl N-oxide, indolinyl N-oxide, isoquinolyl N-oxide,quinazolinyl N-oxide, quinoxalinyl N-oxide, phthalazinyl N-oxide,imidazolyl N-oxide, isoxazolyl N-oxide, oxazolyl N-oxide, thiazolylN-oxide, indolizinyl N-oxide, indazolyl N-oxide, benzothiazolyl N-oxide,benzimidazolyl N-oxide, pyrrolyl N-oxide, oxadiazolyl N-oxide,thiadiazolyl N-oxide, triazolyl N-oxide, tetrazolyl N-oxide,benzothiopyranyl S-oxide, and benzothiopyranyl S,S-dioxide,

[1136] where the R_(1-heteroaryl) group is optionally substituted with1, 2, 3, or 4 groups that are independently:

[1137] (i) C₁-C₆ alkyl optionally substituted with 1, 2, or 3 groupsindependently selected from the group consisting of C₁-C₃ alkyl, —F,—Cl, —Br, —I, —OH, —SH, —NR_(1-a)R_(1-b), —C≡N, —CF₃, and C₁-C₃ alkoxy,

[1138] (ii) C₂-C₆ alkenyl optionally substituted with 1, 2, or 3 groupsthat are independently —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and—NR_(1-a)R_(1-b),

[1139] (iii) C₂-C₆ alkynyl optionally substituted with 1, 2, or 3 groupsthat are independently selected from the group consisting of —F, —Cl,—OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b),

[1140] (iv) —F, —Cl, —Br and —I,

[1141] (v) —C₁-C₆ alkoxy optionally substituted with one, two, or three—F,

[1142] (vi) —(CH₂)₀₋₄—NR_(N-2)R_(N-3),

[1143] (vii) —OH,

[1144] (viii) —C—N,

[1145] (ix) (CH₂)₀₋₄—C₃-C₇ cycloalkyl, optionally substituted with 1, 2,or 3 groups that are independently selected from the group consisting of—F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b),

[1146] (x) (CH₂)₀₋₄—CO-(C₁-C₆ alkyl),

[1147] (xi) (CH₂)₀₋₄—SO₂—NR_(N-2)R_(N-3),

[1148] (xii) (CH₂)₀₋₄—CO—NR_(N-2)R_(N-3),

[1149] (xiii) (CH₂)₀₋₄—SO₂-(C₁-C₆ alkyl),

[1150] (xiv) (CH₂)₀₋₄—N(R_(N-2))—SO₂—, and

[1151] (xv) (CH₂)₀₋₄—N(R_(N-2))—C (O)—,

[1152] (8) —(CH₂)₀₋₄—CO-(C₁-C₁₂ alkyl),

[1153] (9) —(CH₂)₀₋₄—CO-(C₂-C₁₂ alkenyl),

[1154] (10) —(CH₂)₀₋₄—CO-(C₂-C₁₂ alkynyl)

[1155] (11) —(CH₂)₀₋₄—CO—(CH₂)₀₋₄ (C₃-C₇ cycloalkyl)

[1156] (12) —(CH₂)₀₋₄—CO—R_(1-aryl),

[1157] (13) —(CH₂)₀₋₄—CO—R_(1-heteroaryl),

[1158] (14) —(CH₂)₀₋₄—CO—R_(1-heterocycle) wherein

[1159] R_(1-heterocycle) at each occurrence is independently selectedfrom the group consisting of morpholinyl, thiomorpholinyl,thiomorpholinyl S-oxide, thiomorpholinyl S,S-dioxide, piperazinyl,homopiperazinyl, pyrrolidinyl, pyrrolinyl, tetrahydropyranyl,piperidinyl, tetrahydrofuranyl, tetrahydrothienyl, homopiperidinyl,homomorpholinyl, homothiomorpholinyl, homothiomorpholinyl S,S-dioxide,oxazolidinonyl, dihydropyrazolyl, dihydropyrrolyl, dihydropyrazinyl,dihydropyridinyl, dihydropyrimidinyl, dihydrofuryl, dihydropyranyl,tetrahydrothienyl S-oxide, tetrahydrothienyl S,S-dioxide, andhomothiomorpholinyl S-oxide,

[1160] where the R_(1-heterocycle) group is bonded by any atom of theparent R_(1-heterocycle) group substituted by hydrogen such that the newbond to the R_(1-heterocycle) group replaces the hydrogen atom and itsbond, where heterocycle is optionally substituted with 1, 2, 3, or 4groups that are independently:

[1161] (a) C₁-C₆ alkyl optionally substituted with one, two or threesubstituents independently selected from the group consisting of C₁-C₃alkyl, halogen, —OH, —SH, —NR_(1-a)R_(1-b) —C≡N, —CF₃, and C₁-C₃ alkoxy,

[1162] (b) C₂-C₆ alkenyl with one or two double bonds, optionallysubstituted with one, two or three substituents independently selectedfrom the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃alkoxy, and —NR_(1-a)R_(1-b)

[1163] (c) C₂-C₆ alkynyl with one or two triple bonds, optionallysubstituted with one, two or three substituents independently selectedfrom the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃alkoxy, and —NR_(1-a)R_(1-b)

[1164] (d) halogen,

[1165] (e) C₁-C₆ alkoxy,

[1166] (f) —C₁-C₆ alkoxy optionally substituted with one, two, or three—F,

[1167] (g) —NR_(N-2)R_(N-3),

[1168] (h) —OH,

[1169] (i) —C≡N,

[1170] (j ) (CH₂)₀₋₄-(C₃-C₇ cycloalkyl), optionally substituted with 1,2, or 3 groups independently selected from the group consisting of —F,—Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b),

[1171] (k) —(CH₂)₀₋₄—CO-(C₁-C₄ alkyl)

[1172] (l) —(CH₂)₀₋₄—SO₂—NR_(1-a)R_(1-b),

[1173] (m) —(CH₂)₀₋₄—CO—NR_(1-a)R_(1-b),

[1174] (n) —(CH₂)₀₋₄—SO₂-(C₁-C₆ alkyl), and

[1175] (o) ═O,

[1176] (p) —(CH₂)₀₋₄—N(R_(N-2))—SO₂—

[1177] (q) —(CH₂)₀₋₄—N(R_(N-2))—C(O)—

[1178] (15) —(CH₂)₀₋₄—CO—R_(N-4) wherein

[1179] R_(N-4) at each occurrence is independently selected from thegroup consisting of morpholinyl, thiomorpholinyl, pyrrolidinonyl,pyrrolyl, pyrazolyl, thienyl, pyridyl N-oxide, piperazinyl, piperidinyl,homomorpholinyl, homothiomorpholinyl, homothiomorpholinyl S-oxide,homothiomorpholinyl S,S-dioxide, pyrrolinyl and pyrrolidinyl where eachgroup is optionally substituted with 1, 2, 3, or 4 groups that areindependently C₁-C₆ alkyl,

[1180] (16) —(CH₂)₀₋₄—CO₂—R_(N-5) where

[1181] R_(N-5) at each occurrence is independently selected from thegroup consisting of:

[1182] (a) C₁-C₆ alkyl,

[1183] (b) —(CH₂)₀₋₂—(R_(1-aryl))

[1184] (c) C₂-C₆ alkenyl,

[1185] (d) C₂-C₆ alkynyl,

[1186] (e) C₃-C₇ cycloalkyl, and

[1187] (f) —(CH₂)₀₋₄—(R_(1-heteroaryl)),

[1188] (17) —(CH₂)₀₋₄—SO₂—NR_(N-2)R_(N-3)

[1189] (18) —(CH₂)₀₋₄—SO-(C₁-C₈ alkyl),

[1190] (19) —(CH₂)₀₋₄—SO₂-(C₁-C₁₂

[1191] (20) —(CH₂)₀₋₄—SO₂-(C₃-C₇ cycloalkyl),

[1192] (21) —(CH₂)₀₋₄—N(H or R_(N-5))—CO₂—R₅,

[1193] (22) —(CH₂)₀₋₄—N(H or R_(N-5))—CO—N(R_(N-5))₂,

[1194] (23) —(CH₂)₀₋₄—N—CS—N(R_(N-5))₂,

[1195] (24) —(CH₂)₀₋₄—N(—H or R_(N-5))—CO—R_(N-2),

[1196] (25) —(CH₂)₀₋₄—NR_(N-2)R_(N-3),

[1197] (26) —(CH₂)₀₋₄—R_(N-4),

[1198] (27) —(CH₂)₀₋₄—O—CO-(C₁-C₆ alkyl)

[1199] (28) —(CH₂)₀₋₄—O—P(O)—(OR₁₀₀)₂ where R₁₀₀ is independently H orC₁-C₄ alkyl,

[1200] (29) —(CH₂)₀₋₄—O—CO—N(R_(N-5))₂,

[1201] (30) —(CH₂)₀₋₄—O—CS—N (R_(N-5))₂,

[1202] (31) —(CH₂)₀₋₄—O—(R_(N-5)),

[1203] (32) —(CH₂)₀₋₄—O—(R_(N-5))—COOH,

[1204] (33) —(CH₂)₀₋₄—S—(R_(N-5)),

[1205] (34) —(CH₂)₀₋₄—O-(C₁-C₆ alkyl) wherein the alkyl group isoptionally substituted with one, two, three, four, or five substituentsindependently selected from the group consisting of F, Cl, Br, and I,

[1206] (35) —(CH₂)₀₋₄-(C₃-C₈ cycloalkyl),

[1207] (36) C₂-C₆ alkenyl optionally substituted with C₁-C₃ alkyl,halogen, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, or —NR_(1-a)R_(1-b),

[1208] (37) C₂-C₆ alkynyl optionally substituted with C₁-C₃ alkyl, —F,—Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, or —NR_(1-a)R_(1-b),and

[1209] (38) —(CH₂)₀₋₄—N(—H or R_(N-5))—SO₂—R_(N-2);

[1210] (IV) —(CR_(C-x)R_(C-y))₀₋₄—R_(C-heteroaryl) whereinR_(C-heteroaryl) at each occurrence is independently selected from thegroup consisting of pyridinyl, pyrimidinyl, quinolinyl, benzothienyl,indolyl, indolinyl, pryidazinyl, pyrazinyl, isoindolyl, isoquinolyl,quinazolinyl, quinoxalinyl, phthalazinyl, imidazolyl, isoxazolyl,pyrazolyl, oxazolyl, thiazolyl, indolizinyl, indazolyl,benzoisothiazolyl, benzimidazolyl, benzofuranyl, furanyl, thienyl,pyrrolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl,oxazolopyridinyl, isothiazolyl, naphthyridinyl, cinnolinyl, carbazolyl,beta-carbolinyl, isochromanyl, chromanyl, tetrahydroisoquinolinyl,isoindolinyl, isobenzotetrahydrofuranyl, isobenzotetrahydrothienyl,isobenzothienyl, benzoxazolyl, pyridopyridinyl, benzotetrahydrofuranyl,benzotetrahydrothienyl, purinyl, benzodioxolyl, triazinyl, henoxazinyl,phenothiazinyl, pteridinyl, benzothiazolyl, imidazopyridinyl,imidazothiazolyl, dihydrobenzisoxazinyl, benzisoxazinyl, benzoxazinyl,dihydrobenzisothiazinyl, benzopyranyl, benzothiopyranyl, coumarinyl,isocoumarinyl, chromonyl, chromanonyl, tetrahydroquinolinyl,dihydroquinolinyl, dihydroquinolinonyl,dihydroisoquinolinonyl,dihydrocoumarinyl, dihydroisocoumarinyl,isoindolinonyl, benzodioxanyl, benzoxazolinonyl, imidazopyrazolyl,quinazolinonyl, pyrazopyridyl, benzooxadiazolyl, dihydropyrimidinonyl,dihydrobenzofuranonyl,

[1211] where the R_(C-heteroaryl) group is bonded by any atom of theparent R_(C-heteroaryl) group substituted by hydrogen such that the newbond to the R_(C-heteroaryl) group replaces the hydrogen atom and itsbond, where heteroaryl is optionally substituted 1, 2, 3, or 4 groupsthat are independently:

[1212] (1) C₁-C₆ alkyl, optionally substituted with 1, 2, or 3 groupsindependently selected from the group consisting of C₁-C₃ alkyl, —F,—Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b),

[1213] (2) —OH,

[1214] (3) —NO₂,

[1215] (4) —F, —Cl, —Br, —I,

[1216] (5) —CO—OH,

[1217] (6) —C≡N,

[1218] (V) C₂-C₁₀ alkenyl optionally substituted with one, two or threesubstituents independently selected from the group consisting of C₁-C₃alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁-C₆ alkoxy, —O-phenyl,and —NR_(1-a)R_(1-b),

[1219] (VI) C₂-C₁₀ alkynyl optionally substituted with one, two or threesubstituents independently selected from the group consisting of C₁-C₃alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁-C₆ alkoxy, —O-phenyl,and —NR_(1-a)R_(1-b),

[1220] (VII) —(C₁-C₆ alkyl)-O-(C₁-C₆ alkyl)-OH,

[1221] (VIII) —CH₂—NH—CH₂—CH(—O—CH₂—CH₃)₂,

[1222] (IX) —(CH₂)₀₋₆—C(═NR_(1-a)) (NR_(1-a)R_(1-b));

[1223] where R_(N) is

[1224] (I) R_(N-1)—X_(N)— where X_(N) is —CO—, and where R_(N-1) isselected from the group consisting of:

[1225] (A) phenyl, which is optionally substituted with one, two orthree of the following substituents which can be the same or differentand are:

[1226] (1) C₁-C₆ alkyl, optionally substituted with one, two or threesubstituents selected from the group consisting of C₁-C₃ alkyl, —F, —Cl,—Br, —I, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b),

[1227] wherein R_(1-a) and R_(1-b) at each occurrence are independentlyH or C₁-C₆ alkyl,

[1228] (2) —OH,

[1229] (3) —NO₂,

[1230] (4) —F, —Cl, —Br, —I,

[1231] (5) —CO₂H,

[1232] (6) —C≡N

[1233] (7) —(CH₂)₀₋₄—CO—NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) arethe same or different and are selected from the group consisting of:

[1234] (a) —H,

[1235] (b) —C₁-C₈ alkyl optionally substituted with one substituentselected from the group consisting of:

[1236] (i) —OH,

[1237] (ii) —NH₂,

[1238] (iii) phenyl,

[1239] (c) —C₁-C₈ alkyl optionally substituted with 1, 2, or 3 groupsthat are independently —F, —Cl, —Br, or —I,

[1240] (d) —C₃-C₈ cycloalkyl,

[1241] (e) —(C₁-C₂ alkyl)-(C₃-C₈ cycloalkyl),

[1242] (f) —(C₁-C₆ alkyl)-O-(C₁-C₃ alkyl),

[1243] (g) —C₂-C₆ alkenyl,

[1244] (h) —C₂-C₆ alkynyl,

[1245] (i) —C₁-C₆ alkyl chain with one double bond and one triple bond,

[1246] (j) —R_(1-aryl), wherein R_(1-aryl), at each occurrence isindependently phenyl, naphthyl, indanyl, indenyl, dihydronaphthyl, ortetralinyl each of which is optionally substituted with 1, 2, 3, or 4groups that are independently:

[1247] (i) C₁-C₆ alkyl optionally substituted with one, two or threesubstituents independently selected from the group consisting of C₁-C₃alkyl, —F, —Cl, —Br, —I, —OH, —SH, —NR_(1-a)R_(1-b), —C≡N, —CF₃, andC₁-C₃ alkoxy,

[1248] (ii) C₂-C₆ alkenyl with one or two double bonds, optionallysubstituted with one, two or three substituents independently selectedfrom the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃alkoxy, and —NR_(1-a)R_(1-b),

[1249] (iii) C₂-C₆ alkynyl optionally substituted with 1, 2, or 3 groupsthat are independently selected from the group consisting of —F, —Cl,—OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b),

[1250] (iv) —F, Cl, —Br and —I,

[1251] (v) —C₁-C₆ alkoxy optionally substituted with 1, 2, or 3 —F,

[1252] (vi) —NR_(N-2)R_(N-3),

[1253] (vii) —OH,

[1254] (viii) —C≡N,

[1255] (ix) C₃-C₇ cycloalkyl, optionally substituted with 1, 2, or 3groups that are selected from the group consisting of —F, —Cl, —OH, —SH,—C≡N, —CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b),

[1256] (x) —CO-(C₁-C₄ alkyl),

[1257] (xi) —SO₂—NR_(1-a)R_(1-b),

[1258] (xii) —CO—NR_(1-a)R_(1-b), or

[1259] (xiii) —SO₂-(C₁-C₄ alkyl)

[1260] (k) R_(1-heteroaryl), wherein R_(1-heteroaryl), at eachoccurrence is independently selected from the group consisting ofpyridinyl, pyrimidinyl, quinolinyl, benzothienyl, indolyl, indolinyl,pryidazinyl, pyrazinyl, isoindolyl, isoquinolyl, quinazolinyl,quinoxalinyl, phthalazinyl, imidazolyl, isoxazolyl, pyrazolyl, oxazolyl,thiazolyl, indolizinyl, indazolyl, benzothiazolyl, benzimidazolyl,benzofuranyl, furanyl, thienyl, pyrrolyl, oxadiazolyl, thiadiazolyl,triazolyl, tetrazolyl, oxazolopyridinyl, imidazopyridinyl, isothiazolyl,naphthyridinyl, cinnolinyl, carbazolyl, beta-carbolinyl, isochromanyl,chromanyl, tetrahydroisoquinolinyl, isoindolinyl,isobenzotetrahydrofuranyl, isobenzotetrahydrothienyl, isobenzothienyl,benzoxazolyl, pyridopyridinyl, benzotetrahydrofuranyl,benzotetrahydrothienyl, purinyl, benzodioxolyl, triazinyl, phenoxazinyl,phenothiazinyl, pteridinyl, benzothiazolyl, imidazopyridinyl,imidazothiazolyl, dihydrobenzisoxazinyl, benzisoxazinyl, benzoxazinyl,dihydrobenzisothiazinyl, benzopyranyl, benzothiopyranyl, coumarinyl,isocoumarinyl, chromonyl, chromanonyl, pyridinyl-N-oxide,tetrahydroquinolinyl, dihydroquinolinyl, dihydroquinolinonyl,dihydroisoquinolinonyl, dihydrocoumarinyl, dihydroisocoumarinyl,isoindolinonyl, benzodioxanyl, benzoxazolinonyl, pyrrolyl N-oxide,pyrimidinyl N-oxide, pyridazinyl N-oxide, pyrazinyl N-oxide, quinolinylN-oxide, indolyl N-oxide, indolinyl N-oxide, isoquinolyl N-oxide,quinazolinyl N-oxide, quinoxalinyl N-oxide, phthalazinyl N-oxide,imidazolyl N-oxide, isoxazolyl N-oxide, oxazolyl N-oxide, thiazolylN-oxide, indolizinyl N-oxide, indazolyl N-oxide, benzothiazolyl N-oxide,benzimidazolyl N-oxide, pyrrolyl N-oxide, oxadiazolyl N-oxide,thiadiazolyl N-oxide, triazolyl N-oxide, tetrazolyl N-oxide,benzothiopyranyl S-oxide, and benzothiopyranyl S,S-dioxide,

[1261] where the R_(1-heteroaryl) group is optionally substituted with1, 2, 3, or 4 groups that are independently:

[1262] (i) C₁-C₆ alkyl optionally substituted with 1, 2, or 3 groupsindependently selected from the group consisting of C₁-C₃ alkyl, —F,—Cl, —Br, —I, —OH, —SH, —NR_(1-a)R_(1-b), —C≡N, —CF₃, and C₁-C₃ alkoxy,

[1263] (ii) C₂-C₆ alkenyl optionally substituted with 1, 2, or 3 groupsthat are independently —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, or—NR_(1-a)R_(1-b),

[1264] (iii) C₂-C₆ alkynyl optionally substituted with 1, 2, or 3 groupsthat are independently —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, or—NR_(1-a)R_(1-b),

[1265] (iv) —F, —Cl, —Br and —I,

[1266] (v) —C₁-C₆ alkoxy optionally substituted with one, two, or three—F,

[1267] (vi) —(CH₂)₀₋₄—NR_(N-2)R_(N-3),

[1268] (vii) —OH,

[1269] (viii) —C≡N,

[1270] (ix) (CH₂)₀₋₄—C₃-C₇ cycloalkyl, optionally substituted with 1, 2,or 3 groups that are independently selected from the group consisting of—F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b),

[1271] (x) (CH₂)₀₋₄—CO-(C₁-C₆ alkyl),

[1272] (xi) (CH₂)₀₋₄—SO₂—NR_(N-2)R_(N-3),

[1273] (xii) (CH₂)₀₋₄—CO—NR_(N-2)R_(N-3),

[1274] (xiii) (CH₂)₀₋₄—SO₂-(C₁-C₆ alkyl),

[1275] (xiv) (CH₂)₀₋₄—N(R_(N-2))—SO₂—, and

[1276] (xv) (CH₂)₀₋₄—N (R_(N-2))—C (O)—,

[1277] (1) —R_(1-heterocyle), wherein

[1278] R_(1-heterocycle) at each occurrence is independently selectedfrom the group consisting of morpholinyl, thiomorpholinyl,thiomorpholinyl S-oxide, thiomorpholinyl S,S-dioxide, dioxide,piperazinyl, homopiperazinyl, pyrrolidinyl, pyrrolinyl,tetrahydropyranyl, piperidinyl, tetrahydrofuranyl, tetrahydrothienyl,homopiperidinyl, homomorpholinyl, homothiomorpholinyl,homothiomorpholinyl S,S-dioxide, oxazolidinonyl, dihydropyrazolyl,dihydropyrrolyl, dihydropyrazinyl, dihydropyridinyl, dihydropyrimidinyl,dihydrofuryl, dihydropyranyl, tetrahydrothienyl S-oxide,tetrahydrothienyl S,S-dioxide, and homothiomorpholinyl S-oxide, wherethe R_(1-heterocycle) group is bonded by any atom of the parentR_(1-heterocycle) group substituted by hydrogen such that the new bondto the R_(1-heterocycle) group replaces the hydrogen atom and its bond,where heterocycle is optionally substituted with 1, 2, 3, or 4 groupsthat are independently:

[1279] (a) C₁-C₆ alkyl optionally substituted with one, two or threesubstituents independently selected from the group consisting of C₁-C₃alkyl, halogen, —OH, —SH, —NR_(1-a)R_(1-b)—C≡N, —CF₃, and C₁-C₃ alkoxy,

[1280] (b) C₂-C₆ alkenyl with one or two double bonds, optionallysubstituted with one, two or three substituents independently selectedfrom the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃alkoxy, and —NR_(1-a)R_(1-b)

[1281] (c) C₂-C₆ alkynyl with one or two triple bonds, optionallysubstituted with one, two or three substituents independently selectedfrom the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃alkoxy, and —NR_(1-a)R_(1-b)

[1282] (d) halogen,

[1283] (e) C₁-C₆ alkoxy,

[1284] (f) —C₁-C₆ alkoxy optionally substituted with one, two, or three—F,

[1285] (g) —NR_(N-2)R_(N-3),

[1286] (h) —OH,

[1287] (i) —C≡N,

[1288] (j) (CH₂)₀₋₄-(C₃-C₈ cycloalkyl), optionally substituted with 1,2, or 3 groups independently selected from the group consisting of —F,—Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b),

[1289] (k) —(CH₂)₀₋₄—CO-(C₁-C₄ alkyl),

[1290] (l) —(CH₂)₀₋₄—S₂—NR_(1-a)R_(1-b),

[1291] (m) —(CH₂)₀₋₄—CO—NR_(1-a)R_(1-b),

[1292] (n) —(CH₂)₀₋₄—SO₂-(C₁-C₆ alkyl), and

[1293] (o) ═O,

[1294] (p) —(CH₂)₀₋₄—N(R_(N-2))—SO₂—

[1295] (q) —(CH₂)₀₋₄—N (R_(N-2))—C(O)—

[1296] (8) —(CH₂)₀₋₄—CO-(C₁-C₁₂ alkyl),

[1297] (9) —(CH₂)₀₋₄—CO-(C₂-C₁₂ alkenyl)

[1298] (10) —(CH₂)₀₋₄—CO-(C₂-C₁₂ alkynyl)

[1299] (11) —(CH₂)₀₋₄—CO-(C₃-C₈ cycloalkyl)

[1300] (12) —(CH₂)₀₋₄—CO—R_(1-aryl),

[1301] (13) —(CH₂)₀₋₄—CO—R_(1-heteroaryl),

[1302] (14) —(CH₂)₀₋₄—CO—R_(1-heterocycle),

[1303] (15) —(CH₂)₀₋₄—CO—R_(N-4) wherein R_(N-4) is selected from thegroup consisting of phenyl, morpholinyl, thiomorpholinyl, piperazinyl,piperidinyl, homomorpholinyl, homothiomorpholinyl, homothiomorpholinylS-oxide, homothiomorpholinyl S,S-dioxide, pyrrolinyl, thienyl,pyrazolyl, pyridyl N-oxide, oxazolyl, thiazolyl, imidazolyl, andpyrrolidinyl where each group is optionally substituted with one, two,three, or four groups that are independently C₁-C₆ alkyl,

[1304] (16) —(CH₂)₀₋₄—CO—O—R_(N-5) where R_(N-5) is selected from thegroup consisting of:

[1305] (a) C₁-C₆ alkyl,

[1306] (b) —(CH₂)₀₋₂—(R_(1-aryl))

[1307] (c) C₂-C₆ alkenyl,

[1308] (d) C₂-C₆ alkynyl,

[1309] (e) —(CH₂)₀₋₂—C₃-C₈ cycloalkyl,

[1310] (f) —(CH₂)₀₋₂—(R_(1-heteroaryl)) and

[1311] (g) —(CH₂)₀₋₂—(R_(1-heterocycle))

[1312] (17) —(CH₂)₀₋₄—SO₂—NR_(N-2)R_(N-3),

[1313] (18) —(CH₂)₀₋₄—SO-(C₁-C₈ alkyl),

[1314] (19) —(CH₂)₀₋₄—SO₂₋(C₁-C₁₂ alkyl)

[1315] (20) —(CH₂)₀₋₄—SO₂-(C₃-C₈ cycloalkyl)

[1316] (21) —(CH₂)₀₋₄—N(H or R_(N-5))—CO—O—R_(N-5),

[1317] (22) —(CH₂)₀₋₄—N(H or R_(N-5))—CO—N (R_(N-5))₂,

[1318] (23) —(CH₂)₀₋₄—N—CS—N(R_(N-5))₂,

[1319] (24) —(CH₂)₀₋₄—N(H or R_(N-5))—CO—R_(N-2),

[1320] (25) —(CH₂)₀₋₄—NR_(N-2)R_(N-3),

[1321] (26) —(CH₂)₀₋₄—R_(N-4),

[1322] (27) —(CH₂)₀₋₄—O—CO-(C₁-C₆ alkyl)

[1323] (28) —(CH₂)₀₋₄—O—P(O)—(OR₁₀₀)₂ wherein

[1324] R₁₀₀ at each occurrence is independently —H or C₁-C₄ alkyl,

[1325] (29) —(CH₂)₀₋₄—O—CO—N(R_(N-5))₂,

[1326] (30) —(CH₂)₀₋₄—O—CS—N(R_(N-5))₂,

[1327] (31) —(CH₂)₀₋₄—O—(R_(N-5))

[1328] (32) —(CH₂)₀₋₄—O—(R_(N-5))—COOH,

[1329] (33) —(CH₂)₀₋₄—S—(R_(N-5)),

[1330] (34) —(CH₂)₀₋₄—O-(C₁-C₆ alkyl optionally substituted with one,two, three, four, or five of —F),

[1331] (35) C₃-C₈ cycloalkyl,

[1332] (36) C₂-C₆ alkenyl optionally substituted with C₁-C₃ alkyl, —F,—Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, or —NR_(1-a)R_(1-b),

[1333] (37) C₂-C₆ alkynyl optionally substituted with C₁-C₃ alkyl, 13 F,—Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, or —NR_(1-a)R_(1-b),

[1334] (38) —(CH₂)₀₋₄—N(H or R_(N-5))—SO₂—R_(N-2),

[1335] (39) —(CH₂)₁₋₄-(C₃-C₈ cycloalkyl),

[1336] (B) —R_(N-heteroaryl) where R_(N-heteroaryl) is selected from thegroup consisting of pyridinyl, indolyl, indolinyl, isoindolyl,imidazolyl, isoxazolyl, oxazolyl, thiazolyl, indolizinyl andisochromanyl,

[1337] where the R_(N-heteroaryl) group is bonded by any atom of theparent R_(N-heteroaryl) group substituted by hydrogen such that the newbond to the R_(N-heteroaryl) group replaces the hydrogen atom and itsbond, where heteroaryl is optionally substituted with one, two, three,or four of:

[1338] (1) C₁-C₆ alkyl, optionally substituted with one, two or threesubstituents selected from the group consisting of C₁-C₃ alkyl, —F, —Cl,—Br, —I, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b),

[1339] (2) —OH,

[1340] (3) —NO₂,

[1341] (4) —F, —Cl, —Br, —I,

[1342] (5) —CO₂H,

[1343] (6) —C≡N,

[1344] (7) —(CH₂)₀₋₄—CO—NR_(N-2)R_(N-3),

[1345] (8) —(CH₂)₀₋₄—CO-(C₁-C₁₂ alkyl),

[1346] (9) —(CH₂)₀₋₄—CO-(C₂-C₁₂ alkenyl),

[1347] (10) —(CH₂)₀₋₄—CO-(C₂-C₁₂ alkynyl)

[1348] (11) —(CH₂)₀₋₄—CO-(C₃-C₈ cycloalkyl),

[1349] (12) —(CH₂)₀₋₄—CO—R_(1-aryl),

[1350] (13) —(CH₂)₀₋₄—CO—R_(1-heteroaryl),

[1351] (14) —(CH₂)₀₋₄—CO—R_(1-heterocycle),

[1352] (15) —(CH₂)₀₋₄—CO—R_(N-4)

[1353] (16) —(CH₂)₀₋₄—CO—O—R_(N-5)

[1354] (17) —(CH₂)₀₋₄—SO₂—NR_(N-2)R_(N-3),

[1355] (18) —(CH₂)₀₋₄—SO-(C₁-C₈ alkyl)

[1356] (19) —(CH₂)₀₋₄—SO₂₋(C₁-C₁₂ alkyl)

[1357] (20) —(CH₂)₀₋₄—SO₂-(C₃-C₈ cycloalkyl),

[1358] (21) —(CH₂)₀₋₄—N(H or R_(N-5))—CO—O—R_(N-5)

[1359] (22) —(CH₂)₀₋₄—N(H or R_(N-5))—CO—N(R_(N-5))₂,

[1360] (23) —(CH₂)₀₋₄—N—CS—N(R_(N-5))₂,

[1361] (24) —(CH₂)₀₋₄—N(—H or R_(N-5))—CO—R_(N-2),

[1362] (25) —(CH₂)₀₋₄—NR_(N-2)R_(N-3),

[1363] (26) —(CH₂)₀₋₄—R_(N-4),

[1364] (27) —(CH₂)₀₋₄—O—CO-(C₁-C₆ alkyl),

[1365] (28) —(CH₂)₀₋₄—O—P(O)—(OR₁₀₀)₂,

[1366] (29) —(CH₂)₀₋₄—O—CO—N (R_(N-5))₂,

[1367] (30) —(CH₂)₀₋₄—O—CS—N (R_(N-5))₂,

[1368] (31) —(CH₂)₀₋₄—O—(R_(N-5)),

[1369] (32) —(CH₂)₀₋₄—O—(R_(N-5))—COOH,

[1370] (33) —(CH₂)₀₋₄—S—(R_(N-5)),

[1371] (34) —(CH₂)₀₋₄—O-(C₁-C₆ alkyl optionally substituted with one,two, three, four, or five of —F),

[1372] (35) C₃-C₈ cycloalkyl,

[1373] (36) C₂-C₆ alkenyl optionally substituted with C₁-C₃ alkyl, —F,—Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, or —NR_(1-a)R_(1-b),

[1374] (37) C₂-C6 alkynyl optionally substituted with C₁-C₃ alkyl, —F,—Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, or —NR_(1-a)R_(1-b),

[1375] (38) —(CH₂)₀₋₄—N(—H or R_(N-5))—SO₂—R_(N-2),

[1376] (39) —(CH₂)₁₋₄—C₃-C₈ cycloalkyl,

[1377] (C) R_(N-aryl)—W—R_(N-aryl),

[1378] (D) R_(N-aryl)—W—R_(N-heteroaryl),

[1379] (E) R_(N-aryl)—W—R_(1-heterocycle),

[1380] (F) R_(N-heteroaryl)—W—R_(N-aryl),

[1381] (G) R_(N-heteroaryl)—W—R_(N-heteroaryl),

[1382] (H) R_(N-heteroaryl)—W—R_(N-1-heterocycle),

[1383] (I) R_(N-heterocycle)—W—R_(N-aryl),

[1384] (J) R_(N-heterocycle)—W—R_(N-heteroaryl),

[1385] (K) R_(N-heterocycle)—W—R_(N-1-heterocycle),

[1386] where W is

[1387] (13) —(CH₂)₁₋₄—,

[1388] (14) —O—,

[1389] (15) —S(O)₀₋₂—,

[1390] (16) —N(R_(N-5))—,

[1391] (17) —CO—; or

[1392] (18) a bond;

[1393] (II) —CO-(C₁-C₆ alkyl)-M-(C₁-C₆ alkyl), where M is S, SO or SO₂,and wherein each alkyl is unsubstituted or substituted with one, two, orthree of substituents independently selected from the group consistingof:

[1394] (A) —NH—CO-(C₁-C₆ alkyl),

[1395] (B) —NH—CO—O—R_(N-8),

[1396] (C) —NR_(N-2)R_(N-3);

[1397] where R₁ is

[1398] —(CH₂)_(n1)-phenyl, where n₁ is zero or one, and which isoptionally substituted with one, two, three or four of the followingsubstituents on the phenyl ring:

[1399] (A) C₁-C₆ alkyl optionally substituted with one, two or threesubstituents selected from the group consisting of C₁-C₃ alkyl, —F, —Cl,—Br, —I, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b),

[1400] (B) C₂-C₆ alkenyl with one or two double bonds, optionallysubstituted with one, two or three substituents selected from the groupconsisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and—NR_(1-a)R_(1-b),

[1401] (C) C₂-C₆ alkynyl with one or two triple bonds, optionallysubstituted with one, two or three substituents selected from the groupconsisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and—NR_(1-a)R_(1-b),

[1402] (D) —F, Cl, —Br or —I,

[1403] (F) —C₁-C₆ alkoxy optionally substituted with one, two or threeof —F,

[1404] (G) —NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) are as definedbelow,

[1405] (H) —OH,

[1406] (I) —C≡N,

[1407] (J) C₃-C₇ cycloalkyl, optionally substituted with one, two orthree substituents selected from the group consisting of —F, 13 Cl, —OH,—SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b),

[1408] (K) —CO-(C₁-C₄ alkyl),

[1409] (L) —SO₂—NR_(1-a)R_(1-b),

[1410] (M) —CO—NR_(1-a)R_(1-b),

[1411] (N) —SO₂-(C₁-C₄ alkyl); and

[1412] where R₂ is

[1413] (I) —(Z)—C₁-C₆ alkyl, where Z is a bond, —C(O), —CO₂— or —SO₂—,wherein the alkyl group is optionally substituted with one, two or threesubstituents selected from the group consisting of C₁-C₃ alkyl, C₁-C₇alkyl (optionally substituted with C₁-C₃ alkyl and C₁-C₃ alkoxy), —F,—Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, —NR_(1-a)R_(1-b) whereR_(1-a) and R_(1-b) are independently —H or C₁-C6 alkyl, and —OC═ONR_(1-a)R_(1-b),

[1414] (II) —(Z)—CH₂ 13 S(O)₀₋₂-(C₁-C₆ alkyl),

[1415] (III) —(Z)—CH₂—CH₂—S(O)₀₋₂-(C₁-C₆ alkyl)

[1416] (IV) —(Z)—C₂-C₆ alkenyl with one or two double bonds, optionallysubstituted with one, two or three substituents selected from the groupconsisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and—NR_(1-a)R_(1-b),

[1417] (V) —(Z)—C₂-C₆ alkynyl with one or two triple bonds, optionallysubstituted with one, two or three substituents selected from the groupconsisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and—NR_(1-a)R_(1-b),

[1418] (VI) —(Z)—(CH₂)_(n1)—(R_(1-aryl)), where Z is a bond, CO, CO₂ orSO₂, where n₁ is zero or one and where R_(1-aryl) is phenyl, 1-naphthyl,2-naphthyl and indanyl, indenyl, dihydronaphthalyl, or tetralinyloptionally substituted with one, two, three or four of the followingsubstituents on the aryl ring:

[1419] (A) C₁-C₆ alkyl optionally substituted with one, two or threesubstituents selected from the group consisting of C₁-C₃ alkyl, —F, —Cl,—Br, —I, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b),

[1420] (B) C₂-C₆ alkenyl with one or two double bonds, optionallysubstituted with one, two or three substituents selected from the groupconsisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and—NR_(1-a)R_(1-b),

[1421] (C) C₂-C₆ alkynyl with one or two triple bonds, optionallysubstituted with one, two or three substituents selected from the groupconsisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and—NR_(1-a)R_(1-b),

[1422] (D) —F, Cl, —Br or —I,

[1423] (F) —C₁-C₆ alkoxy optionally substituted with one, two or threeof —F,

[1424] (G) —NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) are as definedbelow,

[1425] (H) —OH,

[1426] (I) —C≡N,

[1427] (J) C₃-C₇ cycloalkyl, optionally substituted with one, two orthree substituents selected from the group consisting of —F, —Cl, —OH,—SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b),

[1428] (K) —CO-(C₁-C₄ alkyl),

[1429] (L) —SO₂—NR_(1-a)R_(1-b),

[1430] (M) —CO—NR_(1-a)R_(1-b),

[1431] (N) —SO₂-(C₁-C₄ alkyl)

[1432] (VII) —(Z)—(CH₂)_(n1)—(R_(1-heteroaryl)) where n₁ is as definedabove and where R_(1-heteroaryl) is selected from the group consistingof:

[1433] pyridinyl, pyrimidinyl, quinolinyl, benzothienyl, indolyl,indolinyl, pryidazinyl, pyrazinyl, isoindolyl, isoquinolyl,quinazolinyl, quinoxalinyl, phthalazinyl, imidazolyl, isoxazolyl,pyrazolyl, oxazolyl, thiazolyl, indolizinyl, indazolyl, benzothiazolyl,benzimidazolyl, benzofuranyl, furanyl, thienyl, pyrrolyl, oxadiazolyl,thiadiazolyl, triazolyl, tetrazolyl, oxazolopyridinyl, imidazopyridinyl,isothiazolyl, naphthyridinyl, cinnolinyl, carbazolyl, beta-carbolinyl,isochromanyl, chromanyl, tetrahydroisoquinolinyl, isoindolinyl,isobenzotetrahydrofuranyl, isobenzotetrahydrothienyl, isobenzothienyl,benzoxazolyl, pyridopyridinyl, benzotetrahydrofuranyl,benzotetrahydrothienyl, purinyl, benzodioxolyl, triazinyl, phenoxazinyl,phenothiazinyl, pteridinyl, benzothiazolyl, imidazopyridinyl,imidazothiazolyl, dihydrobenzisoxazinyl, benzisoxazinyl, benzoxazinyl,dihydrobenzisothiazinyl, benzopyranyl, benzothiopyranyl, coumarinyl,isocoumarinyl, chromonyl, chromanonyl, pyridinyl-N-oxide,tetrahydroquinolinyl, dihydroquinolinyl, dihydroquinolinonyl,dihydroisoquinolinonyl, dihydrocoumarinyl, dihydroisocoumarinyl,isoindolinonyl, benzodioxanyl, benzoxazolinonyl, pyrrolyl N-oxide,pyrimidinyl N-oxide, pyridazinyl N-oxide, pyrazinyl N-oxide, quinolinylN-oxide, indolyl N-oxide, indolinyl N-oxide, isoquinolyl N-oxide,quinazolinyl N-oxide, quinoxalinyl N-oxide, phthalazinyl N-oxide,imidazolyl N-oxide, isoxazolyl N-oxide, oxazolyl N-oxide, thiazolylN-oxide, indolizinyl N-oxide, indazolyl N-oxide, benzothiazolyl N-oxide,benzimidazolyl N-oxide, pyrrolyl N-oxide, oxadiazolyl N-oxide,thiadiazolyl N-oxide, triazolyl N-oxide, tetrazolyl N-oxide,benzothiopyranyl S-oxide, benzothiopyranyl S,S-dioxide,

[1434] where the R_(1-heteroaryl) group is bonded to —(CH₂)_(n1)— by anyring atom of the parent R_(N-heteroaryl) group substituted by hydrogensuch that the new bond to the R_(1-heteroaryl) group replaces thehydrogen atom and its bond, where heteroaryl is optionally substitutedwith one, two, three or four of:

[1435] (1) C₁-C₆ alkyl optionally substituted with one, two or threesubstituents selected from the group consisting of C₁-C₃ alkyl, —F, —Cl,—Br, —I, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b),

[1436] (2) C₂-C₆ alkenyl with one or two double bonds, optionallysubstituted with one, two or three substituents selected from the groupconsisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and—NR_(1-a)R_(1-b),

[1437] (3) C₂-C₆ alkynyl with one or two triple bonds, optionallysubstituted with one, two or three substituents selected from the groupconsisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and—NR_(1-a)R_(1-b),

[1438] (4) —F, Cl, —Br or —I,

[1439] (6) —C₁-C₆ alkoxy optionally substituted with one, two, or threeof —F,

[1440] (7) —NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) are as definedbelow,

[1441] (8) —OH,

[1442] (9) —C≡N,

[1443] (10) C₃-C₇ cycloalkyl, optionally substituted with one, two orthree substituents selected from the group consisting of —F, —Cl, —OH,—SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b),

[1444] (11) —CO-(C₁-C₄ alkyl),

[1445] (12) —SO₂—NR_(1-a)R_(1-b),

[1446] (13) —CO—NR_(1-a)R_(1-b), or

[1447] (14) —SO₂-(C₁-C₄ alkyl), with the proviso that when n₁ is zeroR_(1-heteroaryl) is not bonded to the carbon chain by nitrogen, or

[1448] (VIII) —(Z)—(CH₂)_(n1)—(R_(1-heterocycle)) where n₁ is as definedabove and R_(1-heterocycle) is selected from the group consisting of:

[1449] morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide,thiomorpholinyl S,S-dioxide, piperazinyl, homopiperazinyl, pyrrolidinyl,pyrrolinyl, tetrahydropyranyl, piperidinyl, tetrahydrofuranyl,tetrahydrothienyl, homopiperidinyl, homomorpholinyl, homomorpholinylS-oxide, homothiomorpholinyl S,S-dioxide, oxazolidinonyl,dihydropyrazolyl, dihydropyrrolyl dihydropyrazinyl dihydropyridinyldihydropyrimidinyl, dihydrofuryl, dihydropyranyl, tetrahydrothienylS-oxide, tetrahydrothienyl S,S-dioxide, homothiomorpholinyl S-oxide,

[1450] where the R_(1-heterocycle) group is bonded by any atom of theparent R_(1-heterocycle) group substituted by hydrogen such that the newbond to the R_(1-heterocycle) group replaces the hydrogen atom and itsbond, where heterocycle is optionally substituted with one, two, threeor four:

[1451] (1) C₁-C₆ alkyl optionally substituted with one, two or threesubstituents selected from the group consisting of C₁-C₃ alkyl, —F, —Cl,—Br, —I, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b),

[1452] (2) C₂-C₆ alkenyl with one or two double bonds, optionallysubstituted with one, two or three substituents selected from the groupconsisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and—NR_(1-a)R_(1-b),

[1453] (3) C₂-C₆ alkynyl with one or two triple bonds, optionallysubstituted with one, two or three substituents selected from the groupconsisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and—NR_(1-a)R_(1-b),

[1454] (4) —F, Cl, —Br, or —I,

[1455] (5) C₁-C₆ alkoxy,

[1456] (6) —C₁-C₆ alkoxy optionally substituted with one, two, or three—F,

[1457] (7) —NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) are as definedbelow,

[1458] (8) —OH,

[1459] (9) —C≡N,

[1460] (10) C₃-C₇ cycloalkyl, optionally substituted with one, two orthree substituents selected from the group consisting of —F, —Cl, —OH,—SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b),

[1461] (11) —CO-(C₁-C₄ alkyl),

[1462] (12) —SO₂—NR_(1-a)R_(1-b),

[1463] (13) —CO—NR_(1-a)R_(1-b),

[1464] (14) —SO₂-(C₁-C₄ alkyl)

[1465] (15) ═O, with the proviso that when n₁ is zero R_(1-heterocycle)is not bonded to the carbon chain by nitrogen; and

[1466] where R₂₀ is H or C₁₋₆ alkyl or alkenyl.

[1467] The compounds of the invention, and pharmaceutically acceptablesalts or esters thereof, are useful for treating humans who haveAlzheimer's disease, for helping prevent or delay the onset ofAlzheimer's disease, for treating patients with mild cognitiveimpairment (MCI) and preventing or delaying the onset of Alzheimer'sdisease in those who would progress from MCI to AD, for treating Down'ssyndrome, for treating humans who have Hereditary Cerebral Hemorrhagewith Amyloidosis of the Dutch-Type, for treating cerebral amyloidangiopathy and preventing its potential consequences, i.e. single andrecurrent lobar hemorrhages, for treating other degenerative dementias,including dementias of mixed vascular and degenerative origin, dementiaassociated with Parkinson's disease, dementia associated withprogressive supranuclear palsy, dementia associated with cortical basaldegeneration, diffuse Lewy body type of Alzheimer's disease. It ispreferred that the disease is Alzheimer's disease.

[1468] The compounds of the invention are also useful to inhibitbeta-secretase and reduce or inhibit the formation of placque.

[1469] When treating these diseases, compounds of the invention caneither be used individually or together as is best for the patient.

[1470] With regard to these diseases the term “treating” means thatcompounds of the invention can be used in humans with existing disease.The compounds of the invention will not necessarily cure the patient whohas the disease but will delay or slow the progression of the diseasethereby giving the individual a more useful life span.

[1471] The term “preventing” means that that if the compounds of theinvention are administered to those who do not now have the disease butwho would normally get the disease or be at increased risk for thedisease, they will not get the disease. In addition, “preventing” alsoincludes delaying the development of the disease in an individual whowill ultimately get the disease or would be at risk for the disease. Bydelaying the onset of the disease, compounds of the invention haveprevented the individual from getting the disease during the period inwhich the individual would normally have gotten the disease or reducethe rate of development of the disease or some of its effects but forthe administration of compounds of the invention up to the time theindividual ultimately gets the disease.

[1472] In treating or preventing the above diseases the compounds of theinvention are administered in a therapeutically effective amount. Thetherapeutically effective amount will vary depending on the particularcompound used and the route of administration as is known to thoseskilled in the art.

[1473] In treating a patient with any of the diagnosed above conditionsa physician should begin administration of one or more of the compoundsof the invention immediately and continue indefinitely.

[1474] In treating patients who do not at the have Alzheimer's disease,but who are believed to be at substantial risk for getting Alzheimer'sdisease in the future, the physician should start treatment when thepatient first experiences early pre-Alzheimer's symptoms such as, memoryor cognitive problems associated with aging. In addition, there are somepatients who are at high risk because of having the genetic marker APOE4which is predictive for Alzheimer's disease. In these situations, eventhough the patient does not have the disease, the administration of thecompounds of the invention should be started before disease symptomsappear and treatment continued indefinitely to prevent or delay themfrom possibly getting the disease.

[1475] The compounds of the invention can be administered orally,parenterally (IV, IM, depo-IM, SQ and depo-SQ), sublingually,intranasally (inhalation), intrathecally, topically and rectally. Theinvention here is the compounds of the invention. There is nothing newabout the routes of administration nor the dosage forms. Dosage formsknown to those skilled in the art are suitable for delivery of thecompounds of the invention.

[1476] When administered orally, the compounds of the invention can beadministered in usual dosage forms for oral administration as is wellknown to those skilled in the art. These dosage forms include the usualsolid unit dosage forms of tablets and capsules as well as liquid dosageforms such as solutions, suspensions and elixirs. When the solid dosageforms are used, it is preferred that they be of the sustained releasetype so that the compounds of the invention need to be administered onlyonce or twice daily.

[1477] The oral dosage forms are administered to the patient one thrufour times daily. It is preferred that the compounds of the invention beadministered either three or fewer time, more preferably once or twicedaily. Hence, it is preferred that the compounds of the invention beadministered in solid dosage form and further it is preferred that thesolid dosage form be a sustained release form which permits once ortwice daily dosing. It is preferred that whatever dosage form is used,that it be designed so as to protect the compounds of the invention fromthe acidic environment of the stomach. Enteric coated tablets are wellknown to those skilled in the art. In addition, capsules filled withsmall spheres each coated to protect from the acidic stomach, are alsowell known to those skilled in the art. When administered orally thetherapeutically effective amount is from about 0.1 mg/day to about 1,000mg/day. It is preferred that the oral dosage is from about 1 mg/day toabout 100 mg/day. It is more preferred that the oral dosage is fromabout 5 mg/day to about 50 mg/day. It is understood that while a patientmay be started on one dose, that dose may have to be varied over time asthe patient's condition changes.

[1478] The compounds of the invention can be administered parenterally,for example, by IV, IM, depo-IM, SC, or depo-SC. When administeredparenterally, a therapeutically effective amount of about 0.5 to about100 mg/day, preferably from about 5 to about 50 mg daily should bedelivered. When a depot formulation is used for injection once a monthor once every two weeks, the dose should be about 0.5 mg/day to about 50mg/day, or a monthly dose of from about 15 mg to about 1,500 mg. In partbecause of the forgetfulness of the patients with Alzheimer's disease,it is preferred that the parenteral dosage form be a depo formulation.

[1479] The compounds of the invention can be given sublingually. Whengiven sublingually, the compounds of the invention should be given onethru four times daily in the same amount as for TM administration.

[1480] The compounds of the invention can be given intranasally. Whengiven by this route of administration, the appropriate dosage forms area nasal spray or dry powder as is known to those skilled in the art. Thedosage of the compounds of the invention for intranasal administrationis the same as for TM administration.

[1481] The compounds of the invention can be given intrathecally. Whengiven by this route of administration the appropriate dosage form can bea parenteral dosage form as is known to those skilled in the art. Thedosage of the compounds of the invention for intrathecal administrationis the same as for IM administration.

[1482] The compounds of the invention can be administered topically.When given by this route, the appropriate dosage form is a cream,ointment, or patch. Because of the amount of the compounds of theinvention to be administered, the patch is preferred. When administeredtopically, the dosage is from about 0.5 mg/day to about 200 mg/day.Because the amount that can be delivered by a patch is limited, two ormore patches may be used. The number and size of the patch is notimportant, what is important is that a therapeutically effective amountof the compounds of the invention be delivered as is known to thoseskilled in the art. The compounds of the invention can be administeredrectally by suppository as is known to those skilled in the art. Whenadministered by suppository, the therapeutically effective amount isfrom about 0.5 mg to about 500 mg.

[1483] The compounds of the invention can be administered by implants asis known to those skilled in the art. When administering a compound ofthe invention by implant, the therapeutically effective amount is thesame as for depot administration.

[1484] The compounds of the invention are used in the same manner by thesame routes of administration using the same pharmaceutical dosage formsand at the same dosing schedule for treating patients with MCI (mildcognitive impairment) and preventing or delaying the onset ofAlzheimer's disease in those who would progress from MCI to AD, fortreating Down's syndrome, for treating humans who have HereditaryCerebral Hemorrhage with Amyloidosis of the Dutch-Type, for treatingcerebral amyloid angiopathy and preventing its potential consequences,i.e. single and recurrent lobar hemorrhages, for treating otherdegenerative dementias, including dementias of mixed vascular anddegenerative origin, dementia associated with Parkinson's disease,dementia associated with progressive supranuclear palsy, dementiaassociated with cortical basal degeneration, diffuse Lewy body type ofAlzheimer's disease.

[1485] The compounds of the invention can be used with each other orwith other agents used to treat or prevent the conditions listed above.Such agents include gamma-secretase inhibitors, anti-amyloid vaccinesand pharmaceutical agents such as donepezil hydrochloride (ARICEPTTablets), tacrine hydrochloride (COGNEX Capsules) or other acetylcholineesterase inhibitors and with direct or indirectneurotropic agents of thefuture.

[1486] In addition, the compounds of the invention can also be used withinhibitors of P-glycoproten (P-gp). The use of P-gp inhibitors is knownto those skilled in the art. See for example, Cancer Research, 53,4595-4602 (1993), Clin. Cancer Res., 2, 7-12 (1996), Cancer Research,56, 4171-4179 (1996), International Publications WO99/64001 andWO01/10387. The important thing is that the blood level of the P-gpinhibitor be such that it exerts its effect in inhibiting P-gp fromdecreasing brain blood levels of the compounds of the invention. To thatend the P-gp inhibitor and the compounds of the invention can beadministered at the same time, by the same or different route ofadministration, or at different times. The important thing is not thetime of administration but having an effective blood level of the P-gpinhibitor.

[1487] Suitable P-gp inhibitors include cyclosporin A, verapamil,tamoxifen, quinidine, Vitamin E-TGPS, ritonavir, megestrol acetate,progesterone, rapamycin, 10,1 1-methanodibenzosuberane, phenothiazines,acridine derivatives such as GF120918, FK506, VX-710, LY335979, PSC-833,GF-102,918 and other steroids. It is to be understood that additionalagents will be found that do the same function and are also consideredto be useful.

[1488] The P-gp inhibitors can be administered orally, parenterally,(IV, IM, IM- depo, SQ, SQ-depo), topically, sublingually, rectally,intranasally, intrathecally and by implant.

[1489] The therapeutically effective amount of the P-gp inhibitors isfrom about 0.1 to about 300 mg/kg/day, preferably about 0.1 to about 150mg/kg daily. It is understood that while a patient may be started on onedose, that dose may have to be varied over time as the patient'scondition changes.

[1490] When administered orally, the P-gp inhibitors can be administeredin usual dosage forms for oral administration as is known to thoseskilled in the art. These dosage forms include the usual solid unitdosage forms of tablets and capsules as well as liquid dosage forms suchas solutions, suspensions and elixirs. When the solid dosage forms areused, it is preferred that they be of the sustained release type so thatthe P-gp inhibitors need to be administered only once or twice daily.The oral dosage forms are administered to the patient one thru fourtimes daily. It is preferred that the P-gp inhibitors be administeredeither three or fewer times a day, more preferably once or twice daily.Hence, it is preferred that the P-gp inhibitors be administered in soliddosage form and further it is preferred that the solid dosage form be asustained release form which permits once or twice daily dosing. It ispreferred that what ever dosage form is used, that it be designed so asto protect the P-gp inhibitors from the acidic environment of thestomach. Enteric coated tablets are well known to those skilled in theart. In addition, capsules filled with small spheres each coated toprotect From the acidic stomach, are also well known to those skilled inthe art.

[1491] In addition, the P-gp inhibitors can be administeredparenterally. When administered parenterally they can be administeredIV, IM, depo-IM, SQ or depo-SQ. The P-gp inhibitors can be givensublingually. When given sublingually, the P-gp inhibitors should begiven one thru four times daily in the same amount as for IMadministration.

[1492] The P-gp inhibitors can be given intranasally. When given by thisroute of administration, the appropriate dosage forms are a nasal sprayor dry powder as is known to those skilled in the art. The dosage of theP-gp inhibitors for intranasal administration is the same as for IMadministration.

[1493] The P-gp inhibitors can be given intrathecally. When given bythis route of administration the appropriate dosage form can be aparenteral dosage form as is known to those skilled in the art.

[1494] The P-gp inhibitors can be given topically. When given by thisroute ofadministration, the appropriate dosage form is a cream, ointmentor patch. Because of the amount of the P-gp inhibitors needed to beadministered the patch is preferred. However, the amount that can bedelivered by a patch is limited. Therefore, two or more patches may berequired. The number and size of the patch is not important, what isimportant is that a therapeutically effective amount of the P-gpinhibitors be delivered as is known to those skilled in the art.

[1495] The P-gp inhibitors can be administered rectally by suppositoryas is known to those skilled in the art.

[1496] The P-gp inhibitors can be administered by implants as is knownto those skilled in the art.

[1497] Route of administration and the dosage forms for administeringthe P-gp inhibitors are known in the art. Given a particular P-gpinhibitor, and a desired dosage form, one skilled in the art would knowhow to prepare the appropriate dosage form for the P-gp inhibitor.

[1498] It should be apparent to one skilled in the art that the exactdosage and frequency of administration will depend on the particularcompounds of the invention administered, the particular condition beingtreated, the severity of the condition being treated, the age, weight,general physical condition of the particular patient, other medicationthe individual may be taking as is well known to those skilled in theart.

[1499] The compounds of the invention are also useful to inhibitbeta-secretase and reduce or inhibit the formation of plaque.

[1500] Inhibition of APP Cleavage

[1501] The compounds of the invention inhibit cleavage of APP betweenMet595 and Asp596 numbered for the APP695 isoform, or a mutant thereof,or at a corresponding site of a different isoform, such as APP751 orAPP770, or a mutant thereof (sometimes referred to as the “betasecretase site”. While not wishing to be bound by a particular theory,inhibition of beta-secretase activity is thought to inhibit productionof beta amyloid peptide (A-beta or Abeta). Inhibitory activity isdemonstrated in one of a variety of inhibition assays, whereby cleavageof an APP substrate in the presence of A-beta-secretase enzyme isanalyzed in the presence of the inhibitory compound, under conditionsnormally sufficient to result in cleavage at the beta-secretase cleavagesite. Reduction of APP cleavage at the beta-secretase cleavage sitecompared with an untreated or inactive control is correlated withinhibitory activity. Assay systems that can be used to demonstrateefficacy of the compound inhibitors of the invention are known.Representative assay systems are described, for example, in U.S. PatNos. 5,942,400, 5,744,346, as well as in the examples below.

[1502] The enzymatic activity of beta-secretase and the production ofAbeta can be analyzed in vitro or in vivo, using natural, mutated,and/or synthetic APP substrates, natural, mutated, and/or syntheticenzyme, and the test compound. The analysis may involve primary orsecondary cells expressing native, mutant, and/or synthetic APP andenzyme, or may utilize transgenic animal models expressing the substrateand enzyme. Detection of enzymatic activity can be by analysis of one ormore of the cleavage products, for example, by immunoassay, flurometricor chromogenic assay, HPLC, or other means of detection. Inhibitorycompounds are determined as those having the ability to decrease theamount of beta-secretase cleavage product produced in comparison to acontrol, where beta-secretase mediated cleavage in the reaction systemis observed and measured in the absence of inhibitory compounds.

[1503] Beta-secretase

[1504] Various forms of beta-secretase enzyme are known, and areavailable and useful for assay of enzyme activity and inhibition ofenzyme activity. These include native, recombinant, and synthetic formsof the enzyme. Human beta-secretase is known as Beta Site APP CleavingEnzyme (BACE), Asp2, and memapsin 2, and has been characterized, forexample, in U.S. Pat. No. 5,744,346 and published PCT patentapplications WO98/22597, WO00/03819, WO01/23533, and WO00/17369, as wellas in literature publications (Mol.Cell.Neurosci. 14:419-427 (1999);Science 286:735-741 (1999); Nature 402:533-537 (1999); Nature 40:537-540(1999); and PNAS USA 97:1456-1460 (2000)). Synthetic forms of the enzymehave also been described (WO98/22597 and WO00/17369). Beta-secretase canbe extracted and purified from human brain tissue and can be produced incells, for example mammalian cells expressing recombinant enzyme.

[1505] Prefered compounds of the invention are effective to inhibit 50%of beta-secretase enzymatic activity at a concentration of less than 50micromolar, preferably at a concentration of 10 micromolar or less, morepreferably 1 micromolar or less, and most preferably 10 nanomolar orless.

[1506] APP Substrate

[1507] Assays that demonstrate inhibition of beta-secretase-mediatedcleavage of APP can utilize any of the known forms of APP, including the695 amino acid “normal,, isotype described in Nature 325:733-6 (1987),the 770 amino acid isotype described Nature 331:530-532 (1981), andvariants such as the Swedish Mutation (KM670-1NL) (APP-SW), the LondonMutation (V7176F), and others. See, for example U.S. Pat. No. 5,766,846and also Nature Genet. 1:233-234 (1992), for a review of known variantmutations. Additional useful substrates include the dibasic amino acidmodification, APP-KK disclosed, for example, in WO00/17369, fragments ofAPP, and synthetic peptides containing the beta-secretase cleavage site,wild type (WT) or mutated form, e.g., SW, as described, for example, inU.S. Pat. No. 5,942,400 and WO00/03819.

[1508] The APP substrate contains the beta-secretase cleavage site ofAPP (KM-DA or NL-DA) for example, a complete APP peptide or variant, anAPP fragment, a recombinant or synthetic APP, or a fusion peptide.Preferably, the fusion peptide includes the beta-secretase cleavage sitefused to a peptide having a moiety useful forenzymatic assay, forexample, having isolation and/or detection properties. A useful moietymay be an antigenic epitope for antibody binding, a label or otherdetection moiety, a binding substrate, and the like.

[1509] Antibodies

[1510] Products characteristic of APP cleavage can be measured byimmunoassay using various antibodies, as described, for example, inNeuro. Lett. 249:21-4 (1999) and in U.S. Pat. No. 5,612,486. Usefulantibodies to detect Abeta include, for example, the monoclonal antibody6E10 (Senetek, St. Louis, Mo.) that specifically recognizes an epitopeon amino acids 1-16 of the Abeta peptide; antibodies 162 and 164 (NewYork State Institute for Basic Research, Staten Island, N.Y.) that arespecific for human A-beta 1-40 and 1-42, respectively; and antibodiesthat recognize the junction region of beta-amyloid peptide, the sitebetween residues 16 and 17, as described in U.S. Pat. No. 5,593,846.Antibodies raised against a synthetic peptide of residues 591 to 596 ofAPP and SW192 antibody raised against 590-596 of the Swedish mutationare also useful in immunoassay of APP and its cleavage products, asdescribed in U.S. Pat. Nos. 5,604,102 and 5,721,130.

[1511] Assay Systems

[1512] Assays for determining APP cleavage at the beta-secretasecleavage site are well known in the art. Exemplary assays, aredescribed, for example, in U.S. Pat. Nos. 5,744,346 and 5,942,400, anddescribed in the EXAMPLES below.

[1513] Cell Free Assays

[1514] Exemplary assays that can be used to demonstrate the inhibitoryactivity of the compounds of the invention are described, for example,in WO00/17369, WO 00/03819, and U.S. Pat. Nos. 5,942,400 and 5,744,346.Such assays can be performed in cell-free incubations or in cellularincubations using cells expressing A-beta- secretase and an APPsubstrate having A-beta-secretase cleavage site.

[1515] An APP substrate containing the beat-secretase cleavage site ofAPP, for example, a complete APP or variant, an APP fragment, or arecombinant or synthetic APP substrate containing the amino acidsequence: KM-DA or NL-DA, is incubated in the presence of beta-secretaseenzyme, a fragment thereof, or a synthetic or recombinant polypeptidevariant having beta-secretase activity and effective to cleave thebeta-secretase cleavage site of APP, under incubation conditionssuitable for the cleavage activity of the enzyme. Suitable substratesoptionally include derivatives that may be fusion proteins or peptidesthat contain the substrate peptide and a modification useful tofacilitate the purification or detection of the peptide or itsbeta-secretase cleavage products. Useful modifications include theinsertion of a known antigenic epitope for antibody binding; the linkingof a label or detectable moiety, the linking of a binding substrate, andthe like.

[1516] Suitable incubation conditions for a cell-free in vitro assayinclude, for example: approximately 200 nanomolar to 10 micromolarsubstrate, approximately 10 to 200 picomolar enzyme, and approximately0.1 nanomolar to 10 micromolar inhibitor compound, in aqueous solution,at an approximate pH of 4-7, at approximately 37° C., for a time periodof approximately 10 minutes to 3 hours. These incubation conditions areexemplary only, and can be varied as required for the particular assaycomponents and/or desired measurement system. Optimization of theincubation conditions for the particular assay components should accountfor the specific beta-secretase enzyme used and its pH optimum, anyadditional enzymes and/or markers that might be used in the assay, andthe like. Such optimization is routine and will not require undueexperimentation.

[1517] One useful assay utilizes a fusion peptide having maltose bindingprotein (MBP) fused to the C-terminal 125 amino acids of APP-SW. The MBPportion is captured on an assay substrate by anti-MBP capture antibody.Incubation of the captured fusion protein in the presence ofbeta-secretase results in cleavage of the substrate at thebeta-secretase cleavage site. Analysis of the cleavage activity can be,for example, by immunoassay of cleavage products. One such immunoassaydetects a unique epitope exposed at the carboxy terminus of the cleavedfusion protein, for example, using the antibody SW192. This assay isdescribed, for example, in U.S. Pat. No. 5,942,400.

[1518] Cellular Assay

[1519] Numerous cell-based assays can be used to analyze beta-secretaseactivity and/or processing of APP to release A-beta. Contact of an APPsubstrate with A-beta- secretase enzyme within the cell and in thepresence or absence of a compound inhibitor of the invention can be usedto demonstrate beta-secretase inhibitory activity of the compound.Preferably, assay in the presence of a useful inhibitory compoundprovides at least about 30%, most preferably at least about 50%inhibition of the enzymatic activity, as compared with a non-inhibitedcontrol.

[1520] In one embodiment, cells that naturally express beta-secretaseare used. Alternatively, cells are modified to express a recombinantbeta-secretase or synthetic variant enzyme as discussed above. The APPsubstrate may be added to the culture medium and is preferably expressedin the cells. Cells that naturally express APP, variant or mutant formsof APP, or cells transformed to express an isoform of APP, mutant orvariant APP, recombinant or synthetic APP, APP fragment, or syntheticAPP peptide or fusion protein containing the beta-secretase APP cleavagesite can be used, provided that the expressed APP is permitted tocontact the enzyme and enzymatic cleavage activity can be analyzed.

[1521] Human cell lines that normally process Abeta from APP provide auseful means to assay inhibitory activities of the compounds of theinvention. Production and release of A-beta and/or other cleavageproducts into the culture medium can be measured, for example byimmunoassay, such as Western blot or enzyme-linked immunoassay (EIA)such as by ELISA.

[1522] Cells expressing an APP substrate and an active beta-secretasecan be incubated in the presence of a compound inhibitor to demonstrateinhibition of enzymatic activity as compared with a control. Activity ofbeta-secretase can be measured by analysis of one or more cleavageproducts of the APP substrate. For example, inhibition of beta-secretaseactivity against the substrate APP would be expected to decrease releaseof specific beta-secretase induced APP cleavage products such as Abeta.

[1523] Although both neural and non-neural cells process and releaseA-beta, levels of endogenous beta-secretase activity are low and oftendifficult to detect by EIA. The use of cell types known to have enhancedbeta-secretase activity, enhanced processing of APP to Abeta, and/orenhanced production of A-beta are therefore preferred. For example,transfection of cells with the Swedish Mutant form of APP (APP-SW); withAPP-KK; or with APP-SW-KK provides cells having enhanced beta-secretaseactivity and producing amounts of A-beta that can be readily measured.

[1524] In such assays, for example, the cells expressing APP andbeta-secretase are incubated in a culture medium under conditionssuitable for beta-secretase enzymatic activity at its cleavage site onthe APP substrate. On exposure of the cells to the compound inhibitor,the amount of Abeta released into the medium and/or the amount of CTF99fragments of APP in the cell lysates is reduced as compared with thecontrol. The cleavage products of APP can be analyzed, for example, byimmune reactions with specific antibodies, as discussed above.

[1525] Preferred cells for analysis of beta-secretase activity includeprimary human neuronal cells, primary transgenic animal neuronal cellswhere the transgene is APP, and other cells such as those of a stable293 cell line expressing APP, for example, APP-SW.

[1526] In Vivo Assays: Animal Models

[1527] Various animal models can be used to analyze beta-secretaseactivity and/or processing of APP to release Abeta, as described above.For example, transgenic animals expressing APP substrate andbeta-secretase enzyme can be used to demonstrate inhibitory activity ofthe compounds of the invention. Certain transgenic animal models havebeen described, for example, in U.S. Pat. Nos. 5,877,399, 5,612,486,5,387,742, 5,720,936, 5,850,003, 5,877,015 and 5,811,633, and Nature373:523 (1995)). Preferred are animals that exhibit characteristicsassociated with the pathophysiology of AD. Administration of thecompound inhibitors of the invention to the transgenic mice describedherein provides an alternative method for demonstrating the inhibitoryactivity of the compounds. Administration of the compounds in apharmaceutically effective carrier and via an administrative route thatreaches the target tissue in an appropriate therapeutic amount is alsopreferred.

[1528] Inhibition of beta-secretase mediated cleavage of APP at thebeta-secretase cleavage site and of Abeta release can be analyzed inthese animals by measure of cleavage fragments in the animal's bodyfluids such as cerebral fluid or tissues. Analysis of brain tissues forAbeta deposits or plaques is preferred.

[1529] On contacting an APP substrate with A-beta-secretase enzyme inthe presence of an inhibitory compound of the invention and underconditions sufficient to permit enzymatic mediated cleavage of APPand/or release of Abeta from the substrate, the compounds of theinvention are effective to reduce beta-secretase-mediated cleavage ofAPP at the beta-secretase cleavage site and/or effective to reducereleased amounts of Abeta. Where such contacting is the administrationof the inhibitory compounds of the invention to an animal model, forexample, as described above, the compounds are effective to reduce Abetadeposition in brain tissues of the animal, and to reduce the numberand/or size of beta amyloid plaques. Where such administration is to ahuman subject, the compounds are effective to inhibit or slow theprogression of disease characterized by enhanced amounts of Abeta toslow the progression of AD in the, and/or to prevent onset ordevelopment of AD in a patient at risk for the disease.

[1530] Unless defined otherwise, all scientific and technical terms usedherein have the same meaning as commonly understood by one of skill inthe art to which this invention belongs.

[1531] Definitions and Conventions

[1532] The definitions and explanations below are for the terms as usedthroughout this entire document including both the specification and theclaims.

[1533] Definitions

[1534] Pharmaceutically acceptable refers to those properties and/orsubstances which are acceptable to the patient from apharmacological/toxicological point of view and to the manufacturingpharmaceutical chemist from a physical/chemical point of view regardingcomposition, formulation, stability, patient acceptance andbioavailability.

[1535] AD refers to Alzheimer's disease.

[1536] APP, amyloid precursor protein, is defined as any APPpolypeptide, including APP variants, mutations, and isoforms, forexample, as disclosed in U.S. Pat. No. 5,766,846.

[1537] A-beta (or Abeta), amyloid beta peptide, is defined as anypeptide resulting from beta-secretase mediated cleavage of APP,including peptides of 39, 40, 41, 42, and 43 amino acids, and extendingfrom the beta-secretase cleavage site to amino acids 39, 40, 41, 42, or43.

[1538] Beta-secretase (beta-secretase, BACE1, Asp2, Memapsin 2) is anaspartyl protease that mediates cleavage of APP at the amino-terminaledge of Abeta. Human beta-secretase is described, for example, inWO00/17369.

[1539] DMSO refers to dimethyl sulfoxide.

[1540] All temperatures are in degrees Centigrade.

[1541] HPLC refers to high pressure liquid chromatography.

[1542] BOC refers to 1,1-dimethylethoxy carbonyl or t-butoxycarbonyl,—CO—O—C(CH₃)₃.

[1543] Protecting group generally refers to any suitable protectinggroups, compatible with the synthetic routes for preparing the compoundsherein. Generally, suitable protecting groups are those found inProtective Groups in Organic Synthesis, Greene, et. al., 2^(nd) ed.,John Wiley & Sons, 1991; and 3^(rd) ed., John Wiley & Sones, 1999 Morespecific protecting groups are α-methyl benzyl, t-butoxycarbonyl,benzyloxycarbonyl, formyl, trityl, phthalimido, trichloroacetyl,chloroacetyl, bromoacetyl, iodoacetyl, 4-phenylbenzyloxycarbonyl,2-methylenzyloxycarbonyl, 4-ethoxybenzyloxycarbonyl,4-flurorobenzyloxycarbonyl, 4-chlorobenzyloxycarbonyl,3-chlorobenzyloxycarbonyl, 2-chlorobenzyloxycarbonyl,2,4-dichlorobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl,3-bromobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl,4-cyanobenzyloxycarbonyl, 2-(4-xenyl)isopropoxycarbonyl,1,1-diphenyleth-1-yloxycarbonyl, 1,1-diphenylprop-1-yloxycarbonyl,2-phenylprop-2-yloxycarbonyl, 2-(p-toluyl)prop-2-yloxycarbonyl,cyclopentanyloxycarbonyl, 1-methylcycoopentanyloxycarbonyl,cyclohexanyloxycarbonyl, 1-methylcyclohexanyloxycabonyl,2-methylcyclohexanyloxycarbonyl, 2-(4-toluylsulfonyl)ethoxycarbonyl,2-(methylsulfonyl)ethoxycarbonyl, 2-(triphenylphosphino)ethoxycarbonyl,fluorenylmethoxycarbonyl, 2-(trimethylsilyl)ethoxycarbonyl,allyloxycarbonyl, 1-(trimethylsilylmethyl)prop-1-enyloxycarbonyl,5-benzisoxalymethoxycarbonyl, 4-acetoxybenzyloxycarbonyl,2,2,2-trichloroethoxycarbonyl, 2-ethynyl-2-propoxycarbonyl,cyclopropylmethoxycarbonyl, 4-(decyloxyl)benzyloxycarbonyl,isobrornyloxycarbonyl and 1-piperidyloxycarbonyl, 9-fluoroenylmethylcarbonate, —CH—CH═CH₂ and phenyl-C(═N—)—H.

[1544] Saline refers to an aqueous saturated sodium chloride solution.

[1545] Chromatography (column and flash chromatography) refers topurification/separation of compounds expressed as (support, eluent). Itis understood that the appropriate fractions are pooled and concentratedto give the desired compound(s).

[1546] Pharmaceutically acceptable refers to those properties and/orsubstances that are acceptable to the patient from apharmacological/toxicological point of view and to the manufacturingpharmaceutical chemist from a physical/chemical point of view regardingcomposition, formulation, stability, patient acceptance andbioavailability.

[1547] A therapeutically effective amount is defined as an amounteffective to reduce or lessen at least one symptom of the disease beingtreated or to reduce or delay onset of one or more clinical markers orsymptoms of the disease.

[1548] It should be noted that, as used in this specification and theappended claims, the singular forms “a,” “an,” and “the” include pluralreferents unless the content clearly dictates otherwise. Thus, forexample, reference to a composition containing “a compound” includes amixture of two or more compounds. It should also be noted that the term“or” is generally employed in its sense including “and/or” unless thecontent clearly dictates otherwise.

[1549] Unless defined otherwise, all scientific and technical terms usedherein have the same meaning as commonly understood by one of skill inthe art to which this invention belongs.

[1550] All patents and publications referred to herein are herebyincorporated by reference for all purposes.

[1551] Conventions for Formulas and Definitions of Variables

[1552] The chemical formulas representing various compounds or molecularfragments in the specification and claims may contain variablesubstituents in addition to expressly defined structural features. Thesevariable substituents are identified by a letter or a letter followed bya numerical subscript, for example, “Z₁” or “R_(i)” where “i” is aninteger. These variable substituents are either monovalent or bivalent,that is, they represent a group attached to the formula by one or twochemical bonds. For example, a group Z₁ would represent a bivalentvariable if attached to the formula CH₃—C(═Z₁)H. Groups R_(i) and R_(j)would represent monovalent variable substituents if attached to theformula CH₃—CH₂—C(R_(i)) (R_(j))H₂. When chemical formulas are drawn ina linear fashion, such as those above, variable substituents containedin parentheses are bonded to the atom immediately to the left of thevariable substituent enclosed in parentheses. When two or moreconsecutive variable substituents are enclosed in parentheses, each ofthe consecutive variable substituents is bonded to the immediatelypreceding atom to the left which is not enclosed in parentheses. Thus,in the formula above, both R_(i) and R_(j) are bonded to the precedingcarbon atom. Also, for any molecule with an established system of carbonatom numbering, such as steroids, these carbon atoms are designated asC_(i), where “i” is the integer corresponding to the carbon atom number.For example, C₆ represents the 6 position or carbon atom number in thesteroid nucleus as traditionally designated by those skilled in the artof steroid chemistry. Likewise the term “R6” represents a variablesubstituent (either monovalent or bivalent) at the C₆ position.

[1553] Chemical formulas or portions thereof drawn in a linear fashionrepresent atoms in a linear chain. The symbol “−” in general representsa bond between two atoms in the chain. Thus CH₃—O—CH₂—CH(R_(i))—CH₃represents a 2-substituted-1-methoxypropane compound. In a similarfashion, the symbol “=” represents a double bond, e.g.,CH₂═C(R_(i))—O—CH₃, and the symbol “=” represents a triple bond, e.g.,HC≡C—CH(R_(i))—CH₂—CH₃. Carbonyl groups are represented in either one oftwo ways: —CO— or —C(═O)—, with the former being preferred forsimplicity.

[1554] Chemical formulas of cyclic (ring) compounds or molecularfragments can be represented in a linear fashion. Thus, the compound4-chloro-2-methylpyridine can be represented in linear fashion byN*═C(CH₃)—CH═CCl—CH═C*H with the convention that the atoms marked withan asterisk (*) are bonded to each other resulting in the formation of aring. Likewise, the cyclic molecular fragment, 4-(ethyl)-1-piperazinylcan be represented by —N*—(CH₂)₂—N(C₂H₅)—CH₂—C*H₂.

[1555] A rigid cyclic (ring) structure for any compounds herein definesan orientation with respect to the plane of the ring for substituentsattached to each carbon atom of the rigid cyclic compound. For saturatedcompounds which have two substituents attached to a carbon atom which ispart of a cyclic system, —C(X₁) (X₂)— the two substituents may be ineither an axial or e-quatorial position relative to the ring and maychange between axial/equatorial. However, the position of the twosubstituents relative to the ring and each other remains fixed. Whileeither substituent at times may lie in the plane of the ring(equatorial) rather than above or below the plane (axial), onesubstituent is always above the other. In chemical structural formulasdepicting such compounds, a substituent (X₁) which is “below” anothersubstituent (X₂) will be identified as being in the alpha configurationand is identified by a broken, dashed or dotted line attachment to thecarbon atom, i.e., by the symbol “- - - ” or “. . . ”. The correspondingsubstituent attached “above” (X₂) the other (X₁) is identified as beingin the beta configuration and is indicated by an unbroken lineattachment to the carbon atom. When a variable substituent is bivalent,the valences may be taken together or separately or both in thedefinition of the variable. For example, a variable R_(i) attached to acarbon atom as —C(═R_(i))— might be bivalent and be defined as oxo orketo (thus forming a carbonyl group (—CO—) or as two separately attachedmonovalent variable substituents alpha-R_(i-j) and beta-R_(i-k). When abivalent variable, R_(i), is defined to consist of two monovalentvariable substituents, the convention used to define the bivalentvariable is of the form “alpha-R_(i-j):beta-R_(i-k)” or some variantthereof. In such a case both alpha-R_(i-j) and beta-R_(i-k) are attachedto the carbon atom to give —C(alpha-R_(i-j)) (beta-R_(i-k))—. Forexample, when the bivalent variable R₆, —C(═R₆)— is defined to consistof two monovalent variable substituents, the two monovalent variablesubstituents are alpha-R₆₋₁:beta-R₆₋₂, . . . alpha-R₆₋₉:beta-R₆₋₁₀, etc,giving —C(alpha-R6-1) (beta-R₆₋₂)—, . . . —C(alpha-R₆₋₉) (beta-R₆₋₁₀)—,etc. Likewise, for the bivalent variable R₁₁, —C(═R₁₁)—, two monovalentvariable substituents are alpha-R₁₁₋₁:beta-R₁₁₋₂. For a ring substituentfor which separate alpha and beta orientations do not exist (e.g. due tothe presence of a carbon carbon double bond in the ring), and for asubstituent bonded to a carbon atom which is not part of a ring theabove convention is still used, but the alpha and beta designations areomitted.

[1556] Just as a bivalent variable may be defined as two separatemonovalent variable substituents, two separate monovalent variablesubstituents may be defined to be taken together to form a bivalentvariable. For example, in the formula —C₁(R_(i))H—C₂(R_(j))H— (C₁ and C₂define arbitrarily a first and second carbon atom, respectively) R_(i)and R_(j) may be defined to be taken together to form (1) a second bondbetween C₁ and C₂ or (2) a bivalent group such as oxa (—O—) and theformula thereby describes an epoxide. When R_(i) and R_(j) are takentogether to form a more complex entity, such as the group —X—Y—, thenthe orientation of the entity is such that C₁ in the above formula isbonded to X and C₂ is bonded to Y. Thus, by convention the designation“. . . R_(i) and R_(j) are taken together to form —CH₂—CH₂—O—CO— . . . ”means a lactone in which the carbonyl is bonded to C₂. However, whendesignated “. . . R_(j) and R_(i) are taken together to form—CO—O—CH₂—CH₂— the convention means a lactone in which the carbonyl isbonded to C₁.

[1557] The carbon atom content of variable substituents is indicated inone of two ways. The first method uses a prefix to the entire name ofthe variable such as “C₁-C₄”, where both “1” and “4” are integersrepresenting the minimum and maximum number of carbon atoms in thevariable. The prefix is separated from the variable by a space. Forexample, “C₁-C₄ alkyl” represents alkyl of 1 through 4 carbon atoms,(including isomeric forms thereof unless an express indication to thecontrary is given). Whenever this single prefix is given, the prefixindicates the entire carbon atom content of the variable being defined.Thus C₂-C₄ alkoxycarbonyl describes a group CH₃—(CH₂)_(n)-0-CO— where nis zero, one or two. By the second method the carbon atom content ofonly each portion of the definition is indicated separately by enclosingthe “C_(i)-C_(j)” designation in parentheses and placing it immediately(no intervening space) before the portion of the definition beingdefined. By this optional convention (C₁-C₃) alkoxycarbonyl has the samemeaning as C₂-C₄ alkoxycarbonyl because the “C₁-C₃” refers only to thecarbon atom content of the alkoxy group. Similarly while both C₂-C₆alkoxyalkyl and (C₁-C₃) alkoxy(C₁-C₃)alkyl define alkoxyalkyl groupscontaining from 2 to 6 carbon atoms, the two definitions differ sincethe former definition allows either the alkoxy or alkyl portion alone tocontain 4 or 5 carbon atoms while the latter definition limits either ofthese groups to 3 carbon atoms.

[1558] Modes of Preparation

[1559] Compounds of the invention can be prepared utilizing a variety ofknown chemical transformations. In essence, the preparation of thecompounds of formula I may be achieved using techniques and chemicalprocesses analogous to those known in the art; the choice of thespecific route being dependent upon the usual factors in pharmaceuticalresearch institutions such as availability and cost of startingmaterials, time and difficulties in separation and purification ofintermediates and final compounds and such other factors well known andgenerally appreciated by those of ordinary skill in the art. In fact,there will generally be more than one process to prepare the compoundsof the invention. Those having skill in the art will recognize that thestarting materials may be varied and additional steps employed toproduce compounds encompassed by the present invention, as demonstratedby the following examples.

[1560] The starting materials and various intermediates may be obtainedfrom commercial sources, prepared from commercially available organiccompounds, or prepared using well known synthetic methods. In somecases, protection of reactive functionalities may be necessary toachieve some of the transformations. In general, the need for suchprotecting groups as well as the conditions necessary to attach andremove such groups will be apparent to those skilled in the art oforganic synthesis.

[1561] Representative synthetic methodologies suitable for preparing thecompounds of the invention are disclosed in: Tetrahedron Letters, 39,4925-4928 (1998); Journal of Medicinal Chemistry, 41, 3387-3401 (1998);Journal of Medicinal Chemistry, 39, 3203-3216 (1996); and/or Journal ofthe Chemical Society Chemical Communications, 1052-1053 (1993).

[1562] Examples of syntheses for preparing compounds of the inventionare set forth below in Scheme 1, Scheme 2, Scheme 3 and Scheme 4.Specific exemplary descriptions of the routes depicted in Schemes 1-4are found in the synthetic examples given for Intermediates A-D, generalcompound couplings E-G, and examples 1-5 below.

[1563] As used herein, Pg means protecting group, which is as definedherein; for exemplary synthesis of N-protected a-amino aldehydes see:Chem. Rev. 1989, 89, 149.

[1564] The invention is illustrated further by the following exampleswhich are not to be construed as limiting the invention in scope orspirit to the specific procedures described in them.

[1565] Intermediate Syntheses

[1566] A. 2-Methanesulfonylamino-thiazole-4-carboxylic acid

[1567] 2-Methanesulfonylamino-thiazole-4-carboxylic acid methyl ester:To a well stirred solution of methyl 2-amino-thiazole-4-carboxylatehydrobromide (Justus Liebigs Ann. Chem. 1951, 571, 44, Heterocycles1997, 45, 1299) (13 g, 51 mmol) and TEA (40 mL, 290 mmol) in DCM (130mL) at rt was added methanesulfonyl chloride (11 mL, 140 mmol) dropwise.After stirring for 1 h, the reaction mixture was filtered and thefiltrate concentrated. The residue was re-suspended in ethyl acetate,filtered and chromatographed on silica gel (ethyl acetate/ethanol, 97:3)to provide 2-methanesulfonylamino-thiazole-4-carboxylic acid methylester (5.5 g). MS (ESI−) for C₆H₈N₂O₄S₂ m/z 234.9 (M−H)⁻.

[1568] 2-Methanesulfonylamino-thiazole-4-carboxylic acid: A mixture of2-methanesulfonylamino-thiazole-4-carboxylic acid methyl ester (5.5 g,22 mmol) in 1M NaOH (50 mL) was stirred at rt for 1 h. The reactionmixture was extracted with ethyl acetate, concentrated andchromatographed on silica gel (ethyl acetate/ethanol, 97:3) to provide2-methanesulfonylamino-thiazole-4-carboxylic acid (3.7 g) as a solid. MS(ESI−) for C₅H₆N₂O₄S₂ m/z 220.9 (M−H)⁻.

[1569] B. tert-Butyl2-((2R,3S)-3-amino-2-hydroxy-4-phenylbutyl)-2-ethylhydrazinecarboxylate

[1570] N′-Ethylidene-hydrazinecarboxylic acid tert-butyl ester: Asolution of tert-butyl carbazate (50.0 g, 0.38 mole) and acetaldehyde(17.5 g, 0.4 mole) in ethanol (250 mL) was refluxed for 72 h. Thesolution was concentrated in vacuo and dissolved in ethyl acetate. Thesolution was washed with water, dried (anhydrous sodium sulfate) andconcentrated to afford N′-ethylidene-hydrazinecarboxylic acid tert-butylester (56 g) as a light yellow oil that solidified on standing. MS(ESI+) for C₇H₁₄N₂O₂ m/z 159.0 (M+H)⁺.

[1571] N′-Ethylhydrazinecarboxylic acid tert-butyl ester: A slurry ofN′-ethylidene-hydrazinecarboxylic acid tert-butyl ester (5.0 g, 32mmol), acetic acid (48 μL) and PtO₂ (250 mg) in ethanol (50 mL) wasshaken under a 40 psi pressure of H₂ in a Parr hydrogenator for 24 h.The mixture was filtered through Celite to provideN′-ethylhydrazinecarboxylic acid tert-butyl ester (5 g) as a clear oil.MS (ESI+) for C₇H₁₆N₂O₂ m/z 161.0 (M+H)⁺.

[1572] tert-Butyl2-((2R,3S)-3-{[(benzyloxy)carbonyl]amino}-2-hydroxy-4-phenylbutyl)-2-ethylhydrazinecarboxylate(J. Med. Chem. 1998, 41, 3387-3401): To a well stirred solution of[(1S)-1-(2S)-oxiranyl-2-phenylethyl]-carbamic acid phenylmethyl ester(6.07 g, 20.4 mmol) in isopropanol (100 mL) was addedN′-ethylhydrazinecarboxylic acid tert-butyl ester (3.93 g, 24.5 mmol)and the reaction refluxed for 67 h. The reaction was concentrated andchromatographed on silica gel (elution with a gradiant from hexane todichloromethane to 1% methanol saturated with ammonia indichloromethane) to give tert-butyl2-((2R,3S)-3-{[(benzyloxy)carbonyl]amino}-2-hydroxy-4-phenylbutyl)-2-ethylhydrazinecarboxylate(7.9 g) as a white solid. MS (ESI+) for C₂₅H₃₅N₃O₅ m/z 458.3 (M+H)⁺.

[1573] tert-Butyl2-((2R,3S)-3-amino-2-hydroxy-4-phenylbutyl)-2-ethylhydrazinecarboxylate:A solution of tert-butyl2-((2R,3S)-3-{[(benzyloxy)carbonyl]amino}-2-hydroxy-4-phenylbutyl)-2-ethylhydrazinecarboxylate(3.11 g, 6.8 mmol) in methanol (50 mL) was added to 10% Pd/C (0.32 g)and stirred in a hydrogen atmosphere (@ ambient pressure) for 5 h. Thereaction was filtered through Celite and the filtrate concentrated underreduced pressure to yield tert-butyl2-((2R,3S)-3-amino-2-hydroxy-4-phenylbutyl)-2-ethylhydrazinecarboxylate(2.2 g) as an oil. MS (ESI+) for C₁₇H₂₉N₃O₃ m/z 324.3 (M+H)⁺.

[1574] C. tert-Butyl2-((2S,3S)-3-amino-2-hydroxy-4-phenylbutyl)-2-ethylhydrazinecarboxylate

[1575] tert-Butyl2-((2S,3S)-3-{[(benzyloxy)carbonyl]amino}-2-hydroxy-4-phenylbutyl)-2-ethylhydrazinecarboxylate:To a well stirred solution of[(1S)-1-(2R)-oxiranyl-2-phenylethyl]-carbamic acid phenylmethyl ester(312 mg, 1.0 mmol) in isopropanol (3 mL) was addedN′-ethylhydrazinecarboxylic acid tert-butyl ester (202 mg, 1.3 mmol) andthe reaction refluxed for 24 h. The reaction was concentrated to givecrude tert-butyl2-((2S,3S)-3-{[(benzyloxy)carbonyl]amino]-2-hydroxy-4-phenylbutyl)-2-ethylhydrazinecarboxylate(537 mg). MS (ESI+) for C₂₅H₃₅N₃O₅ m/z 458.1 (M+H)⁺.

[1576] tert-Butyl2-((2S,3S)-3-amino-2-hydroxy-4-phenylbutyl)-2-ethylhydrazinecarboxylate:A solution of crude tert-butyl2-((2S,3S)-3-{[(benzyloxy)carbonyl]amino}-2-hydroxy-4-phenylbutyl)-2-ethylhydrazinecarboxylate(502 mg, 1.1 mmol) in MeOH (10 mL) was added to 10% Pd/C (5.2 mg) andstirred in a hydrogen atmosphere (@ ambient pressure) for 6 h. Thereaction was filtered through Celite and the filtrate concentrated underreduced pressure to yield crude tert-butyl2-((2S,3S)-3-amino-2-hydroxy-4-phenylbutyl)-2-ethylhydrazinecarboxylate(293 mg). MS (ESI+) for C₁₇H₂₉N₃O₃ m/z 324.2 (M+H)⁺.

[1577] D. tert-Butyl2-((2S,3S)-3-amino-2-hydroxy-4-(3,5-difluorophenyl)butyl)-2-ethylhydrazinecarboxylate

[1578] (Z)-2-Benzyloxycarbonylamino-3-phenyl-acrylate: A well stirredsolution of 3,5-difluorobenzaldehyde (1.92 g, 13.5 mmol) and methylbenzyloxycarbonylamino-(dimethoxyphosphoryl)acetate (5.37 g, 16.2 mmol)in dry THF (20 mL), under N₂, was cooled to 0° C. and1,1,3,3-tetramethylgaunidine (1.38 g, 16.2 mmol) added via syringe. Thereaction was allowed to warm to rt and stir for 6 h, quenched withsaturated ammonium chloride and extracted with ethyl acetate. Afterconcentration, the residue was chromatographed on silica gel (elutionwith 20% ethyl acetate/heptane) to give methyl(Z)-2-benzyloxycarbonylamino-3-phenyl-acrylate (3.55 g) as a whitesolid. MS (ESI+) for C₁₈H₁₅F₂NO₄ m/z 348.2 (M+H)⁺.

[1579] CBZ-L-3,5-Difluorophenylalanine Methyl Ester: A Parr Hastelloybomb was charged with (Z)-2-benzyloxycarbonylamino-3-phenyl-acrylate (21g, 48 mmol) in degassed methanol (315 mL) and pressurized with H₂ @ 80psi. After 1 h, (S)-EtDuPHOSRh(COD)BF₄ (476 mg, 1.5 mol %) in degassedmethanol (15 mL) was added and the reaction stirred at rt under 40 psiH₂ for 16 h. The solution was filtered through Celite, concentrated andchromatographed on silica gel (elution with 20% ethyl acetate/heptane)to give 20 g of CBZ-L-3,5-difluorophenylalanine methyl ester as a whitesolid. MS (ESI+) for C₁₈H₁₇F₂NO₄ m/z 350.1 (M+H)⁺.

[1580] [1S-(1-(3,5-Difluorobenzyl)-2-hydroxy-ethyl)]-carbamic acidbenzyl ester: To a well stirred solution of L-3,5-difluorophenylalaninemethyl ester (795 mg, 2.3 mmol) and lithium chloride (97 mg, 2.3 mmol)in THF/ethanol (10 mL, 1:1), under N₂, was added solid sodiumborohydride (86 mg, 2.3 mmol) and the reaction stirred at rt overnight.The mixture was quenched with saturated ammonium chloride, extractedwith ethyl acetate and the extracts combined, dried (anhydrous sodiumsulfate) and concentrated. The residue was chromatographed an silica gel(elution with 20% ethyl acetate/heptane) to give[1S-(1-(3,5-difluorobenzyl)-2-hydroxy-ethyl)]-carbamic acid benzyl ester(660 mg) as a white solid. MS (ESI+) for C₁₇H₁₇F₂NO₃ m/z 322.2 (M+H)⁺.

[1581] [1S-(1-(3,5-difluorobenzyl)-2-oxo-ethyl)]-carbamic acid benzylester: To a cold (−78 ° C.) well-stirred solution of oxalyl chloride(0.16 mL, 1.8 mmol) in methylene chloride (20 mL) was added DMSO (0. 13mL, 1.8 mmol) followed by the slow addition of[1S-(1-(3,5-difluoro-benzyl)-2-hydroxy-ethyl)]-carbamic acid benzylester (1.5 mmol)as a solution in CH₂Cl₂ (10 mL). The reaction mixturewas stirred at −78° C. for 10 minutes followed by the addition of Et₃N(0.63 mL, 4.5 mmol, 3.0 equiv). The mixture was stirred at −78° C. untilno starting material was observed by TLC (2 h). The reaction mixture wasthen washed with 10% citric acid (aq) and dried over MgSO₄, filtered andcondensed. The white solid was purified by silica chromatography (20% to50% EtOAc/Heptane) to yield[1S-(1-(3,5-difluorobenzyl)-2-oxo-ethyl)]-carbamic acid benzyl ester(445 mg) as a white solid. MS (ESI+) for C₁₇H₁₅F₂NO₃ m/z 320 (M+H)⁺.

[1582] [1S-(1-(3,5-Difluorobenzyl)-2-propenyl)]-carbamic acid benzylester: To a slurry of diethyl ether (5 mL) and Mg turnings (0.17 g, 7.1mmol) was added ClCH₂Si(CH₃)₃ (0.97 mL, 7.0 mmol) and the mixture washeated to reflux. After initiation (0.5 h @ reflux), the reactionmixture was removed from heating and stirred for an additional 1 h, thencooled to rt. To the cooled solution was[1S-(1-(3,5-difluoro-benzyl)-2-oxo-ethyl)]-carbamic acid benzyl ester(0.45 g, 1.4 mmol) as a solution in distilled THF (10 mL). The reactionmixture was stirred at rt for 1 h, cooled to 0° C. and BF₃(OEt)₂ (0.97mL, 7.0 mmol) added. The reaction mixture was further stirred at rt for16 h, quenched with. 10% NaOH (aq) (50 mL) and stirring continued for 1h. The reaction mixture was extracted with CH₂Cl₂, dried over MgSO_(4,)filtered and condensed to yield a clear oil. The oil was purified bysilica chromatography (20% to 50% EtOAc/heptane) to yield[1S-(1-(3,5-difluorobenzyl)-2-propenyl)]-carbamic acid benzyl ester (270mg) as a white solid. MS (ESI+) for C₁₈H₁₈F₂NO₂ m/z 318 (M+H)⁺.

[1583] [(1S)-1-(2R)-oxiranyl-2-(3,5-difluorophenyl)ethyll-carbamic acidphenylmethyl ester: To CH₂Cl₂ (20 mL) was added[1S-(1-(3,5-difluoro-benzyl)-2-propenyl)]-carbamic acid benzyl ester(270 mg, 0.85 mmol) followed by M-CPBA (77%, 458 mg, 1.0 mmol). Thereaction mixture was stirred at rt for 24 h. The reaction was dilutedwith CH₂Cl₂ and then washed with 10% sodium thiosulfate (aq), dried overNa₂SO₄, filtered and condensed. Preparative chromatography (5×50 cmChiralcel OD, 30° C., 70 ml/min. 25% IPA/75% heptane) provided[(1S)-1-(2R)-oxiranyl-2-(3,5-difluorophenyl)ethyl]-carbamic acidphenylmethyl ester. MS (ESI+) for C₁₈H₁₈F₂NO₃ m/z 334.2 (M+H)⁺.

[1584] tert-Butyl2-((2S,3S)-3-{[(benzyloxy)carbonyl]amino}-2-hydroxy-4-(3,5-difluorophenyl)butyl)-2-ethylhydrazinecarboxylate:To a well stirred solution of[(1S)-1-(2R)-oxiranyl-2-(3,5-difluorophenyl)ethyl]-carbamic acidphenylmethyl ester (496 mg, 1.5 mmol) in isopropanol (4.25 mL) was addedN′-ethylhydrazinecarboxylic acid tert-butyl ester (575 mg, 3.6 mmol) andthe reaction refluxed for 48 h. The reaction was concentrated to providecrude tert-butyl2-((2S,3S)-3-{[(benzyloxy)carbonyl]amino}-2-hydroxy-4-(3,5-difluorophenyl)butyl)-2-ethylhydrazine-carboxylate.MS (ESI+) for C₂₅H₃₃F₂N₃O₅ m/z 516.2 (M+Na)⁺.

[1585] tert-Butyl2-((2S,3S)-3-amino-2-hydroxy-4-(3,5-difluorophenyl)butyl-2-ethylhydrazinecarboxylate:A solution of crude tert-butyl2-((2S,3S)-3-{[(benzyloxy)carbonyl]-amino}-2-hydroxy-4-(3,5-difluorophenyl)butyl)-2-ethylhydrazinecarboxylate(906 mg, 1.8 mmol) in MeOH (15 mL) was added to 10% Pd/C (95 mg) andstirred in a hydrogen atmosphere (ambient pressure) for 4 h. Thecatalyst was filtered off over Celite and the filtrate was concentratedunder reduced pressure to yield crude tert-butyl2-((2S,3S)-3-amino-2-hydroxy-4-(3,5difluorophenyl)butyl)-2-ethylhydrazinecarboxylate.MS (ESI+) for C₁₇H₂₇F₂N₃O₃ m/z 360.2 (M+H)⁺.

[1586] E. N-Terminal Acid Coupling (R_(N))

[1587] Solutions of each acid (R_(N)) were prepared (1.08 mmol) in DMF(3 mL) (enough for 6 cartridges per acid). Solutions of PyBOP (3.74 g,7.2 mmol) and HOBT (0.96 g, 7.2 mmol) in DMF (24 mL) were prepared. Toeach cartridge on a Bohdan block was added acid solution (0.5 niL, 0.18mmol) according to product layout (6 cartridges of each of the 8 acids).To each cartridge was added the PyBOP/HOBT solution (0.5 mL, 0.078 gPYBOP, 0.15 mmol/0.02 g HOBT, 0.15 mmol) and DIEA (0.052 mL, 0.30 mmol).The Bohdan block was agitated on a Bohdan shaker at 700-800 rpm for 1 h.A solution of amine was prepared (2.30 g, 7.2 mmol) in 24 mL of CH₂Cl₂.To each cartridge was added 0.5 mL of amine solution (0.48 g, 0.15mmol). The Bohdan block was agitated on the Bohdan shaker at 700-800 rpmfor 16 h. The reaction mixtures were drained into 48 well Robbin'sblocks. Each cartridge was rinsed with 0.5 mL DMF into another 48 wellRobbin's block. The reaction mixtures were concentrated in the Robbin'sblocks under reduced pressure at 50° C. for 6 h in a Jouan centrifugalevaporator. Products were carried on crude to next reaction.

[1588] F. Deprotection (J. Org. Chem. 1998, 63, 3471)

[1589] Add Dowex 50W×2-400 ion-exchange resin (˜230 mg) to each cleancartridge on a Bohdan block using an Argo Scoop. The previous productwas pipetted as a solution in 2 mL MeOH into each cartridge. The Bohdanblock was agitated on a Bohdan shaker at 50° C. at 700-800 rpm for 4 h.Each cartridge was rinsed with CH₂Cl₂ (2×2.5 mL) and MeOH (10×2.5 mL).The products were eluted using 3.5M NH₃ in MeOH (2×3 mL) into 2 separate48 well Robbin's blocks. Reaction mixtures were concentrated in theRobbin's blocks under reduced pressure at 40° C. for 4 h in a Jouan.

[1590] G. C-Terminal Acid Coupling (R₂)

[1591] Solutions of each acid (R₂) were prepared (1.80 mmol) in DMF (2mL) (enough for 8 cartridges per acid). A solution of HATU (4.13 g, 10.8mmol) in DMF (12 mL) was prepared. To each cartridge on a Bohdan blockwas added acid solution (0.25 mL, 0.225 mmol) according to productlayout (8 cartridges of each of the 6 acids). To each cartridge wasadded 0.25 mL of the HATU solution (0.086 g, 0.225 mmol) and DIEA (0.163mL, 0.94 mmol). The Bohdan block was agitated on a Bohdan shaker at700-800 rpm for 1 h. Solution of the amines were prepared (0.15 mmol/mL)in DMF. To each cartridge was added the amine solution (0.15 mmol,)according to the product layout. The Bohdan block was agitated on theBohdan shaker at 700-800 rpm for 16 h. The reaction mixtures weredrained into 48 well Robbin's blocks. Each cartridge was rinsed with 0.5mL DMF into another 48 well Robbin's block. The reaction mixtures wereconcentrated in the Robbin's blocks under reduced pressure at 50° C. for6 h in a Jouan. Products were dissolved in 2 mL MeOH and eachtransferred to a Varian Mega BE-SCX (2 gm, 12 mL) cartridge that hadbeen presoaked with MeOH (5 mL). After products were loaded onto SCXcartridges by gravity, each cartridge was washed with MeOH (9×5 mL)using vacuum filtration. Final products were eluted off by gravity using3.5M NH₃ in MeOH (3×3 mL) into pre-tared vials.

EXAMPLES Example 1

[1592]N-[(1S,2R)-3-(2-benzoyl-1-ethylhydrazino)-1-benzyl-2-hydroxypropyl]-2-[(methylsulfonyl)amino]-1,3-thiazole-4-carboxamide:Synthesized as described above from tert-butyl2-((2R,3S)-3-amino-2-hydroxy-4-phenylbutyl)-2-ethylhydrazinecarboxylate,benzoic acid and 2-methanesulfonylamino-thiazole-4-carboxylic acid. MS(ESI+) for C₂₄H₂₉N₅O₅S₂ m/z 532.7 (M+H)⁺.

Example 2

[1593]N-{(1S,2R)-1-benzyl-3-[1-ethyl-2-(4-methylpentanoyl)hydrazino]-2-hydroxypropyl}-2-[(methylsulfonyl)amino]-1,3-thiazole-4-carboxamide:Synthesized as described above from tert-butyl2-((2R,3S)-3-amino-2-hydroxy-4-phenylbutyl)2-2-ethylhydrazinecarboxylate,4-methylpentanoic acid and 2-methanesulfonylamino-thiazole-4-carboxylicacid.. MS (ESI+) for C₂₃H₃₅N₅O₅S₂ m/z 526.7 (M+H)⁺.

Example 3

[1594]N¹-{(1S,2S)-1-benzyl-3-[1-ethyl-2-(4-methylpentanoyl)hydrazino]-2-hydroxypropyl}-5-methyl-N³,N³-dipropylisophthalamide: Synthesized as described above fromtert-butyl2-((2S,3S)-3-amino-2-hydroxy-4-phenylbutyl)-2-ethylhydrazinecarboxylate,4-methylpentanoic acid and 5-methyl-N,N-dipropyl-isophthalamic acid (WO02/02512). MS (ESI+) for C₃₃H₅₀N₄O₄ m/z 567.3 (M+H)⁺.

Example 4

[1595]N¹-{(1S,2S)-1-(3,5-difluorobenzyl)-3-[l-ethyl-2-(4-methylpentanoyl)hydrazino]-2-hydroxypropyl}-5-methyl-N³,N³-dipropylisophthalamide:Synthesized as described above from tert-butyl2-((2S,3S)-3-amino-2-hydroxy-4-(3,5difluorophenyl)butyl)-2-ethylhydrazinecarboxylate,3-methylpentanoic acid and 5-methyl-N,N-dipropyl-isophthalamic acid. MS(ESI+) for C₃₃H₄₈F₂N₄O₄ m/z 603.3 (M+H)⁺.

Example 5

[1596]N¹-{(1S,2S)-1-(3,5-difluorobenzyl)-3-[l-ethyl-2-(4-methylbutanoyl)hydrazino]-2-hydroxypropyl}-5-methyl-N³,N³-dipropylisophthalamide:Synthesized as described above from tert-butyl2-((2S,3S)-3-amino-2-hydroxy-4-(3,5difluorophenyl)butyl)-2-ethylhydrazinecarboxylate,3-methylbutanoic acid and 5-methyl-N,N-dipropyl-isophthalamic acid. MS(ESI+) for C₃₂H₄₆F₂N₄O₄ m/z 589.3 (M+H)⁺.

Example 6

[1597] The following compounds, as shown in Table 1 below, are preparedessentially according to the procedures outlined in Schemes 1-4 andaccording to examples 1-5: TABLE 1

1:A1 1, 1, 1, 1

1:A2 1, 1, 1, 2

1:A3 1, 1, 1, 3

1:A4 1, 1, 1, 4

1:A5 1, 1, 2, 1

1:A6 1, 1, 2, 2

1:A7 1, 1, 2, 3

1:A8 1, 1, 2, 4

1:A9 1, 1, 3, 1

1:A10 1, 1, 3, 2

1:A11 1, 1, 3, 3

1:A12 1, 1, 3, 4

1:B1 1, 1, 4, 1

1:B2 1, 1, 4, 2

1:B3 1, 1, 4, 3

1:B4 1, 1, 4, 4

1:B5 1, 2, 1, 1

1:B6 1, 2, 1, 2

1:B7 1, 2, 1, 3

1:B8 1, 2, 1, 4

1:B9 1, 2, 2, 1

1:B10 1, 2, 2, 2

1:B11 1, 2, 2, 3

1:B12 1, 2, 2, 4

1:C1 1, 2, 3, 1

1:C2 1, 2, 3, 2

1:C3 1, 2, 3, 3

1:C4 1, 2, 3, 4

1:C5 1, 2, 4, 1

1:C6 1, 2, 4, 2

1:C7 1, 2, 4, 3

1:C8 1, 2, 4, 4

1:C9 1, 3, 1, 1

1:C10 1, 3, 1, 2

1:C11 1, 3, 1, 3

1:C12 1, 3, 1, 4

1:D1 1, 3, 2, 1

1:D2 1, 3, 2, 2

1:D3 1, 3, 2, 3

1:D4 1, 3, 2, 4

1:D5 1, 3, 3, 1

1:D6 1, 3, 3, 2

1:D7 1, 3, 3, 3

1:D8 1, 3, 3, 4

1:D9 1, 3, 4, 1

1:D10 1, 3, 4, 2

1:D11 1, 3, 4, 3

1:D12 1, 3, 4, 4

1:E1 1, 4, 1, 1

1:E2 1, 4, 1, 2

1:E3 1, 4, 1, 3

1:E4 1, 4, 1, 4

1:E5 1, 4, 2, 1

1:E6 1, 4, 2, 2

1:E7 1, 4, 2, 3

1:E8 1, 4, 2, 4

1:E9 1, 4, 3, 1

1:E10 1, 4, 3, 2

1:E11 1, 4, 3, 3

1:E12 1, 4, 3, 4

1:F1 1, 4, 4, 1

1:F2 1, 4, 4, 2

1:F3 1, 4, 4, 3

1:F4 1, 4, 4, 4

1:F5 1, 5, 1, 1

1:F6 1, 5, 1, 2

1:F7 1, 5, 1, 3

1:F8 1, 5, 1, 4

1:F9 1, 5, 2, 1

1:F10 1, 5, 2, 2

1:F11 1, 5, 2, 3

1:F12 1, 5, 2, 4

1:G1 1, 5, 3, 1

1:G2 1, 5, 3, 2

1:G3 1, 5, 3, 3

1:G4 1, 5, 3, 4

1:G5 1, 5, 4, 1

1:G6 1, 5, 4, 2

1:G7 1, 5, 4, 3

1:G8 1, 5, 4, 4

1:G9 1, 6, 1, 1

1:G10 1, 6, 1, 2

1:G11 1, 6, 1, 3

1:G12 1, 6, 1, 4

1:H1 1, 6, 2, 1

1:H2 1, 6, 2, 2

1:H3 1, 6, 2, 3

1:H4 1, 6, 2, 4

1:H5 1, 6, 3, 1

1:H6 1, 6, 3, 2

1:H7 1, 6, 3, 3

1:H8 1, 6, 3, 4

1:H9 1, 6, 4, 1

1:H10 1, 6, 4, 2

1:H11 1, 6, 4, 3

1:H12 1, 6, 4, 4

2:A1 2, 1, 1, 1

2:A2 2, 1, 1, 2

2:A3 2, 1, 1, 3

2:A4 2, 1, 1, 4

2:A5 2, 1, 2, 1

2:A6 2, 1, 2, 2

2:A7 2, 1, 2, 3

2:A8 2, 1, 2, 4

2:A9 2, 1, 3, 1

2:A10 2, 1, 3, 2

2:A11 2, 1, 3, 3

2:A12 2, 1, 3, 4

2:B1 2, 1, 4, 1

2:B2 2, 1, 4, 2

2:B3 2, 1, 4, 3

2:B4 2, 1, 4, 4

2:B5 2, 2, 1, 1

2:B6 2, 2, 1, 2

2:B7 2, 2, 1, 3

2:B8 2, 2, 1, 4

2:B9 2, 2, 2, 1

2:B10 2, 2, 2, 2

2:B11 2, 2, 2, 3

2:B12 2, 2, 2, 4

2:C1 2, 2, 3, 1

2:C2 2, 2, 3, 2

2:C3 2, 2, 3, 3

2:C4 2, 2, 3, 4

2:C5 2, 2, 4, 1

2:C6 2, 2, 4, 2

2:C7 2, 2, 4, 3

2:C8 2, 2, 4, 4

2:C9 2, 3, 1, 1

2:C10 2, 3, 1, 2

2:C11 2, 3, 1, 3

2:C12 2, 3, 1, 4

2:D1 2, 3, 2, 1

2:D2 2, 3, 2, 2

2:D3 2, 3, 2, 3

2:D4 2, 3, 2, 4

2:D5 2, 3, 3, 1

2:D6 2, 3, 3, 2

2:D7 2, 3, 3, 3

2:D8 2, 3, 3, 4

2:D9 2, 3, 4, 1

2:D10 2, 3, 4, 2

2:D11 2, 3, 4, 3

2:D12 2, 3, 4, 4

2:E1 2, 4, 1, 1

2:E2 2, 4, 1, 2

2:E3 2, 4, 1, 3

2:E4 2, 4, 1, 4

2:E5 2, 4, 2, 1

2:E6 2, 4, 2, 2

2:E7 2, 4, 2, 3

2:E8 2, 4, 2, 4

2:E9 2, 4, 3, 1

2:E10 2, 4, 3, 2

2:E11 2, 4, 3, 3

2:E12 2, 4, 3, 4

2:F1 2, 4, 4, 1

2:F2 2, 4, 4, 2

2:F3 2, 4, 4, 3

2:F4 2, 4, 4, 4

2:F5 2, 5, 1, 1

2:F6 2, 5, 1, 2

2:F7 2, 5, 1, 3

2:F8 2, 5, 1, 4

2:F9 2, 5, 2, 1

2:F10 2, 5, 2, 2

2:F11 2, 5, 2, 3

2:F12 2, 5, 2, 4

2:G1 2, 5, 3, 1

2:G2 2, 5, 3, 2

2:G3 2, 5, 3, 3

2:G4 2, 5, 3, 4

2:G5 2, 5, 4, 1

2:G6 2, 5, 4, 2

2:G7 2, 5, 4, 3

2:G8 2, 5, 4, 4

2:G9 2, 6, 1, 1

2:G10 2, 6, 1, 2

2:G11 2, 6, 1, 3

2:G12 2, 6, 1, 4

2:H1 2, 6, 2, 1

2:H2 2, 6, 2, 2

2:H12 2, 6, 4, 4

3:A1 3, 1, 1, 1

3:A2 3, 1, 1, 2

3:A3 3, 1, 1, 3

3:A4 3, 1, 1, 4

3:A5 3, 1, 2, 1

3:A6 3, 1, 2, 2

3:A7 3, 1, 2, 3

3:A8 3, 1, 2, 4

3:B8 3, 2, 1, 4

3:B9 3, 2, 2, 1

3:B10 3, 2, 2, 2

3:B11 3, 2, 2, 3

3:B12 3, 2, 2, 4

3:C1 3, 2, 3, 1

3:C2 3, 2, 3, 2

3:C3 3, 2, 3, 3

3:C4 3, 2, 3, 4

3:C5 3, 2, 4, 1

3:C6 3, 2, 4, 2

3:C7 3, 2, 4, 3

3:C8 3, 2, 4, 4

3:C9 3, 3, 1, 1

3:C10 3, 3, 1, 2

3:C11 3, 3, 1, 3

3:C12 3, 3, 1, 4

3:D1 3, 3, 2, 1

3:D2 3, 3, 2, 2

3:D3 3, 3, 2, 3

3:D4 3, 3, 2, 4

3:D5 3, 3, 3, 1

3:D6 3, 3, 3, 2

3:D7 3, 3, 3, 3

3:D8 3, 3, 3, 4

3:D9 3, 3, 4, 1

3:D10 3, 3, 4, 2

3:D11 3, 3, 4, 3

3:D12 3, 3, 4, 4

3:E1 3, 4, 1, 1

3:E2 3, 4, 1, 2

3:E3 3, 4, 1, 3

3:E4 3, 4, 1, 4

3:E5 3, 4, 2, 1

3:E6 3, 4, 2, 2

3:E7 3, 4, 2, 3

3:E8 3, 4, 2, 4

3:E9 3, 4, 3, 1

3:E10 3, 4, 3, 2

3:E11 3, 4, 3, 3

3:E12 3, 4, 3, 4

3:F1 3, 4, 4, 1

3:F2 3, 4, 4, 2

3:F3 3, 4, 4, 3

3:F4 3, 4, 4, 4

3:F5 3, 5, 1, 1

3:F6 3, 5, 1, 2

3:F7 3, 5, 1, 3

3:F8 3, 5, 1, 4

3:F9 3, 5, 2, 1

3:F10 3, 5, 2, 2

3:F11 3, 5, 2, 3

3:F12 3, 5, 2, 4

3:G1 3, 5, 3, 1

3:G2 3, 5, 3, 2

3:G3 3, 5, 3, 3

3:G4 3, 5, 3, 4

3:G5 3, 5, 4, 1

3:G6 3, 5, 4, 2

3:G7 3, 5, 4, 3

3:G8 3, 5, 4, 4

3:G9 3, 6, 1, 1

3:G10 3, 6, 1, 2

3:G11 3, 6, 1, 3

3:G12 3, 6, 1, 4

3:H1 3, 6, 2, 1

3:H2 3, 6, 2, 2

3:H3 3, 6, 2, 3

3:H4 3, 6, 2, 4

3:H5 3, 6, 3, 1

3:H6 3, 6, 3, 2

3:H7 3, 6, 3, 3

3:H8 3, 6, 3, 4

3:H9 3, 6, 4, 1

3:H10 3, 6, 4, 2

3:H11 3, 6, 4, 3

3:H12 3, 6, 4, 4 Change of itinerary “FCA681.2” With location, precursor

1:A1 1, 1, 1, 1

1:A2 1, 1, 1, 2

1:A3 1, 1, 1, 3

1:A4 1, 1, 1, 4

1:A5 1, 1, 2, 1

1:A6 1, 1, 2, 2

1:A7 1, 1, 2, 3

1:A8 1, 1, 2, 4

1:A9 1, 1, 3, 1

1:A10 1, 1, 3, 2

1:A11 1, 1, 3, 3

1:A12 1, 1, 3, 4

1:B1 1, 1, 4, 1

1:B2 1, 1, 4, 2

1:B3 1, 1, 4, 3

1:B4 1, 1, 4, 4

1:B5 1, 2, 1, 1

1:B6 1, 2, 1, 2

1:B7 1, 2, 1, 3

1:B8 1, 2, 1, 4

1:B9 1, 2, 2, 1

1:B10 1, 2, 2, 2

1:B11 1, 2, 2, 3

1:B12 1, 2, 2, 4

1:C1 1, 2, 3, 1

1:C2 1, 2, 3, 2

1:C3 1, 2, 3, 3

1:C4 1, 2, 3, 4

1:C5 1, 2, 4, 1

1:C6 1, 2, 4, 2

1:C7 1, 2, 4, 3

1:C8 1, 2, 4, 4

1:C9 1, 3, 1, 1

1:C10 1, 3, 1, 2

1:C11 1, 3, 1, 3

1:C12 1, 3, 1, 4

1:D1 1, 3, 2, 1

1:D2 1, 3, 2, 2

1:D3 1, 3, 2, 3

1:D4 1, 3, 2, 4

1:D5 1, 3, 3, 1

1:D6 1, 3, 3, 2

1:D7 1, 3, 3, 3

1:D8 1, 3, 3, 4

1:D9 1, 3, 4, 1

1:D10 1, 3, 4, 2

1:D11 1, 3, 4, 3

1:D12 1, 3, 4, 4

1:E1 1, 4, 1, 1

1:E2 1, 4, 1, 2

1:E3 1, 4, 1, 3

1:E4 1, 4, 1, 4

1:E5 1, 4, 2, 1

1:E6 1, 4, 2, 2

1:E7 1, 4, 2, 3

1:E8 1, 4, 2, 4

1:E9 1, 4, 3, 1

1:E10 1, 4, 3, 2

1:E11 1, 4, 3, 3

1:E12 1, 4, 3, 4

1:F1 1, 4, 4, 1

1:F2 1, 4, 4, 2

1:F3 1, 4, 4, 3

1:F4 1, 4, 4, 4

1:F5 1, 5, 1, 1

1:F6 1, 5, 1, 2

1:F7 1, 5, 1, 3

1:F8 1, 5, 1, 4

1:F9 1, 5, 2, 1

1:F10 1, 5, 2, 2

1:F11 1, 5, 2, 3

1:F12 1, 5, 2, 4

1:G1 1, 5, 3, 1

1:G2 1, 5, 3, 2

1:G3 1, 5, 3, 3

1:G4 1, 5, 3, 4

1:G5 1, 5, 4, 1

1:G6 1, 5, 4, 2

1:G7 1, 5, 4, 3

1:G8 1, 5, 4, 4

1:G9 1, 6, 1, 1

1:G10 1, 6, 1, 2

1:G11 1, 6, 1, 3

1:G12 1, 6, 1, 4

1:H1 1, 6, 2, 1

1:H2 1, 6, 2, 2

1:H3 1, 6, 2, 3

1:H4 1, 6, 2, 4

1:H5 1, 6, 3, 1

1:H6 1, 6, 3, 2

1:H7 1, 6, 3, 3

1:H8 1, 6, 3, 4

1:H9 1, 6, 4, 1

1:H10 1, 6, 4, 2

1:H11 1, 6, 4, 3

1:H12 1, 6, 4, 4

2:A1 2, 1, 1, 1

2:A2 2, 1, 1, 2

2:A3 2, 1, 1, 3

2:A4 2, 1, 1, 4

2:A5 2, 1, 2, 1

2:A6 2, 1, 2, 2

2:A7 2, 1, 2, 3

2:A8 2, 1, 2, 4

2:A9 2, 1, 3, 1

2:A10 2, 1, 3, 2

2:A11 2, 1, 3, 3

2:A12 2, 1, 3, 4

2:B1 2, 1, 4, 1

2:B2 2, 1, 4, 2

2:B3 2, 1, 4, 3

2:B4 2, 1, 4, 4

2:B5 2, 2, 1, 1

2:B6 2, 2, 1, 2

2:B7 2, 2, 1, 3

2:B8 2, 2, 1, 4

2:B9 2, 2, 2, 1

2:B10 2, 2, 2, 2

2:B11 2, 2, 2, 3

2:B12 2, 2, 2, 4

2:C1 2, 2, 3, 1

2:C2 2, 2, 3, 2

2:C3 2, 2, 3, 3

2:C4 2, 2, 3, 4

2:C5 2, 2, 4, 1

2:C6 2, 2, 4, 2

2:C7 2, 2, 4, 3

2:C8 2, 2, 4, 4

2:C9 2, 3, 1, 1

2:C10 2, 3, 1, 2

2:C11 2, 3, 1, 3

2:C12 2, 3, 1, 4

2:D1 2, 3, 2, 1

2:D2 2, 3, 2, 2

2:D3 2, 3, 2, 3

2:D4 2, 3, 2, 4

2:D5 2, 3, 3, 1

2:D6 2, 3, 3, 2

2:D7 2, 3, 3, 3

2:D8 2, 3, 3, 4

2:D9 2, 3, 4, 1

2:D10 2, 3, 4, 2

2:D11 2, 3, 4, 3

2:D12 2, 3, 4, 4

2:E1 2, 4, 1, 1

2:E2 2, 4, 1, 2

2:E3 2, 4, 1, 3

2:E4 2, 4, 1, 4

2:E5 2, 4, 2, 1

2:E6 2, 4, 2, 2

2:E7 2, 4, 2, 3

2:E8 2, 4, 2, 4

2:E9 2, 4, 3, 1

2:E10 2, 4, 3, 2

2:E11 2, 4, 3, 3

2:E12 2, 4, 3, 4

2:F1 2, 4, 4, 1

2:F2 2, 4, 4, 2

2:F3 2, 4, 4, 3

2:F4 2, 4, 4, 4

2:F5 2, 5, 1, 1

2:F6 2, 5, 1, 2

2:F7 2, 5, 1, 3

2:F8 2, 5, 1, 4

2:F9 2, 5, 2, 1

2:F10 2, 5, 2, 2

2:F11 2, 5, 2, 3

2:F12 2, 5, 2, 4

2:G1 2, 5, 3, 1

2:G2 2, 5, 3, 2

2:G3 2, 5, 3, 3

2:G4 2, 5, 3, 4

2:G5 2, 5, 4, 1

2:G6 2, 5, 4, 2

2:G7 2, 5, 4, 3

2:G8 2, 5, 4, 4

2:G9 2, 6, 1, 1

2:G10 2, 6, 1, 2

2:G11 2, 6, 1, 3

2:G12 2, 6, 1, 4

2:H1 2, 6, 2, 1

2:H2 2, 6, 2, 2

2:H3 2, 6, 2, 3

3:H4 2, 6, 2, 4

3:H5 2, 6, 3, 1

3:H6 2, 6, 3, 2

3:H7 2, 6, 3, 3

3:H8 2, 6, 3, 4

3:H9 2, 6, 4, 1

3:H10 2, 6, 4, 2

3:H11 2, 6, 4, 3

3:H12 2, 6, 4, 4

3:A1 3, 1, 1, 1

3:A2 3, 1, 1, 2

3:A3 3, 1, 1, 3

3:A4 3, 1, 1, 4

3:A5 3, 1, 2, 1

3:A6 3, 1, 2, 2

3:A7 3, 1, 2, 3

3:A8 3, 1, 2, 4

3:A9 3, 1, 3, 1

3:A10 3, 1, 3, 2

3:A11 3, 1, 3, 3

3:A12 3, 1, 3, 4

3:B1 3, 1, 4, 1

3:B2 3, 1, 4, 2

3:B3 3, 1, 4, 3

3:B4 3, 1, 4, 4

3:B5 3, 2, 1, 1

3:B6 3, 2, 1, 2

3:B7 3, 2, 1, 3

3:B8 3, 2, 1, 4

3:B9 3, 2, 2, 1

3:B10 3, 2, 2, 2

3:B11 3, 2, 2, 3

3:B12 3, 2, 2, 4

3:C1 3, 2, 3, 1

3:C2 3, 2, 3, 2

3:C3 3, 2, 3, 3

3:C4 3, 2, 3, 4

3:C5 3, 2, 4, 1

3:C6 3, 2, 4, 2

3:C7 3, 2, 4, 3

3:C8 3, 2, 4, 4

3:C9 3, 3, 1, 1

3:C10 3, 3, 1, 2

3:C11 3, 3, 1, 3

3:C12 3, 3, 1, 4

3:D1 3, 3, 2, 1

3:D2 3, 3, 2, 2

3:D3 3, 3, 2, 3

3:D4 3, 3, 2, 4

3:D5 3, 3, 3, 1

3:D6 3, 3, 3, 2

3:D7 3, 3, 3, 3

3:D8 3, 3, 3, 4

3:D9 3, 3, 4, 1

3:D10 3, 3, 4, 2

3:D11 3, 3, 4, 3

3:D12 3, 3, 4, 4

3:E1 3, 4, 1, 1

3:E2 3, 4, 1, 2

3:E3 3, 4, 1, 3

3:E4 3, 4, 1, 4

3:E5 3, 4, 2, 1

3:E6 3, 4, 2, 2

3:E7 3, 4, 2, 3

3:E8 3, 4, 2, 4

3:E9 3, 4, 3, 1

3:E10 3, 4, 3, 2

3:E11 3, 4, 3, 3

3:E12 3, 4, 3, 4

3:F1 3, 4, 4, 1

3:F2 3, 4, 4, 2

3:F3 3, 4, 4, 3

3:F4 3, 4, 4, 4

3:F5 3, 5, 1, 1

3:F6 3, 5, 1, 2

3:F7 3, 5, 1, 3

3:F8 3, 5, 1, 4

3:F9 3, 5, 2, 1

3:F10 3, 5, 2, 2

3:F11 3, 5, 2, 3

3:F12 3, 5, 2, 4

3:G1 3, 5, 3, 1

3:G2 3, 5, 3, 2

3:G3 3, 5, 3, 3

3:G4 3, 5, 3, 4

3:G5 3, 5, 4, 1

3:G6 3, 5, 4, 2

3:G7 3, 5, 4, 3

3:G8 3, 5, 4, 4

3:G9 3, 6, 1, 1

3:G10 3, 6, 1, 2

3:G11 3, 6, 1, 3

3:G12 3, 6, 1, 4

3:H1 3, 6, 2, 1

3:H2 3, 6, 2, 2

3:H3 3, 6, 2, 3

3:H4 3, 6, 2, 4

3:H5 3, 6, 3, 1

3:H6 3, 6, 3, 2

3:H7 3, 6, 3, 3

3:H8 3, 6, 3, 4

3:H9 3, 6, 4, 1

3:H10 3, 6, 4, 2

3:H11 3, 6, 4, 3

3:H12 3, 6, 4, 4

[1598] The compounds of the invention may exist as geometric orstereoisomers isomers as well as tautomers. Thus, the invention includesall tautomers and geometric isomers, such as the E and Z geometricisomers, as well as mixtures thereof. Furthermore, the inventionincludes pure enantiomers and diasteriomers as well as mixtures thereof,including racemic mixtures. The individual geometric isomers,enantiomers, or diasteriomers may be prepared or isolated by methodsknown in the art.

[1599] Compounds of the invention of designated stereochemistry may beincluded in mixtures, including racemic mixtures, with otherenantiomers, diasteriomers, geometric isomers or tautomers. Compounds ofthe invention with designated stereochemistry are typically present inthese mixtures in excess of 50 percent. Preferably, compounds of theinvention with designated stereochemistry are present in these mixturesin excess of 80 percent. Most preferably, compounds of the inventionwith designated stereochemistry are present in these mixtures in excessof 90 percent.

[1600] Several of the compounds of formula (I) above are amines, and assuch form salts when reacted with acids. Pharmaceutically acceptablesalts are generally preferred over the corresponding amines of theinvention since they typically produce compounds which are more watersoluble, stable and/or more crystalline. Pharmaceutically acceptablesalts are any salt which retains the activity of the parent compound anddoes not impart any deleterious or undesirable effect on the subject towhom it is administered and in the context in which it is administered.Pharmaceutically acceptable salts include salts of both inorganic andorganic acids. The preferred pharmaceutically acceptable salts includesalts of the following acids acetic, aspartic, benzenesulfonic, benzoic,bicarbonic, bisulfuric, bitartaric, butyric, calcium edetate, camsylic,carbonic, chlorobenzoic, citric, edetic, edisylic, estolic, esyl,esylic, formic, fumaric, gluceptic, gluconic, glutamic,glycollylarsanilic, hexamic, hexylresorcinoic, hydrabamic, hydrobromic,hydrochloric, hydroiodic, hydroxynaphthoic, isethionic, lactic,lactobionic, maleic, malic, malonic, mandelic, methanesulfonic,methylnitric, methylsulfuric, mucic, muconic, napsylic, nitric, oxalic,p-nitromethanesulfonic, pamoic, pantothenic, phosphoric, monohydrogenphosphoric, dihydrogen phosphoric, phthalic, polygalactouronic,propionic, salicylic, stearic, succinic, succinic, sulfamic, sulfanilic,sulfonic, sulfuric, tannic, tartaric, teoclic and toluenesulfonic. Forother acceptable salts, see Int. J. Pharm., 33, 201-217 (1986) and J.Pharm. Sci., 66(1), 1, (1977).

[1601] The invention provides compounds, compositions, kits, and methodsfor inhibiting beta-secretase enzyme activity and A beta peptideproduction. Inhibition of beta-secretase enzyme activity halts orreduces the production of A beta from APP and reduces or eliminates theformation of beta-amyloid deposits in the brain.

[1602] Methods of the Invention

[1603] As previously mentioned, compounds of the invention, andpharmaceutically acceptable salts or esters thereof, are useful fortreating humans or animals suffering from a condition characterized by apathological form of beta-amyloid peptide, such as beta-amyloid plaques,and for helping to prevent or delay the onset of such a condition. Forexample, the compounds are useful for treating Alzheimer's disease, forhelping prevent or delay the onset of Alzheimer's disease, for treatingpatients with MCI (mild cognitive impairment) and preventing or delayingthe onset of Alzheimer's disease in those who would progress from MCI toAD, for treating Down's syndrome, for treating humans who haveHereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-Type, fortreating cerebral amyloid angiopathy and preventing its potentialconsequences, i.e. single and recurrent lobal hemorrhages, for treatingother degenerative dementias, including dementias of mixed vascular anddegenerative origin, dementia associated with Parkinson's disease,dementia associated with progressive supranuclear palsy, dementiaassociated with cortical basal degeneration, and diffuse Lewy body typeAlzheimer's disease. The compounds and compositions of the invention areparticularly useful for treating or preventing Alzheimer's disease. Whentreating or preventing these diseases, the compounds of the inventioncan either be used individually or in combination, as is best for thepatient.

[1604] To prepare compositions, one or more compounds of the inventionare mixed with a suitable pharmaceutically acceptable carrier. Uponmixing or addition of the compound(s), the resulting mixture may be asolution, suspension, emulsion, or the like. Liposomal suspensions mayalso be suitable as pharmaceutically acceptable carriers. These may beprepared according to methods known to those skilled in the art. Theform of the resulting mixture depends upon a number of factors,including the intended mode of administration and the solubility of thecompound in the selected carrier or vehicle. The effective concentrationis sufficient for lessening or ameliorating at least one symptom of thedisease, disorder, or condition treated and may be empiricallydetermined.

[1605] Pharmaceutical carriers or vehicles suitable for administrationof the compounds provided herein include any such carriers known tothose skilled in the art to be suitable for the particular mode ofadministration. In addition, the active materials can also be mixed withother active materials that do not impair the desired action, or withmaterials that supplement the desired action, or have another action.The compounds may be formulated as the sole pharmaceutically activeingredient in the composition or may be combined with other activeingredients.

[1606] Where the compounds exhibit insufficient solubility, methods forsolubilizing may be used. Such methods are known and include, but arenot limited to, using cosolvents such as dimethylsulfoxide (DMSO), usingsurfactants such as Tween®, and dissolution in aqueous sodiumbicarbonate. Derivatives of the compounds, such as salts or prodrugs mayalso be used in formulating effective pharmaceutical compositions.

[1607] The concentration of the compound is effective for delivery of anamount upon administration that lessens or ameliorates at least onesymptom of the disorder for which the compound is administered.Typically, the compositions are formulated for single dosageadministration.

[1608] The compounds of the invention may be prepared with carriers thatprotect them against rapid elimination from the body, such astime-release formulations or coatings. Such carriers include controlledrelease formulations, such as, but not limited to, microencapsulateddelivery systems. The active compound is included in thepharmaceutically acceptable carrier in an amount sufficient to exert atherapeutically useful effect in the absence of undesirable side effectson the patient treated. The therapeutically effective concentration maybe determined empirically by testing the compounds in known in vitro andin vivo model systems for the treated disorder.

[1609] The compounds and compositions of the invention can be enclosedin multiple or single dose containers. The enclosed compounds andcompositions can be provided in kits, for example, including componentparts that can be assembled for use. For example, a compound inhibitorin lyophilized form and a suitable diluent may be provided as separatedcomponents for combination prior to use. A kit may include a compoundinhibitor and a second therapeutic agent for co-administration. Theinhibitor and second therapeutic agent may be provided as separatecomponent parts. A kit may include a plurality of containers, eachcontainer holding one or more unit dose of the compound of theinvention. The containers are preferably adapted for the desired mode ofadministration, including, but not limited to tablets, gel capsules,sustained-release capsules, and the like for oral administration; depotproducts, pre-filled syringes, ampoules, vials, and the like forparenteral administration; and patches, medipads, creams, and the likefor topical administration.

[1610] The concentration of active compound in the drug composition willdepend on absorption, inactivation, and excretion rates of the activecompound, the dosage schedule, and amount administered as well as otherfactors known to those of skill in the art.

[1611] The active ingredient may be administered at once, or may bedivided into a number of smaller doses to be administered at intervalsof time. It is understood that the precise dosage and duration oftreatment is a function of the disease being treated and may bedetermined empirically using known testing protocols or by extrapolationfrom in vivo or in vitro test data. It is to be noted thatconcentrations and dosage values may also vary with the severity of thecondition to be alleviated. It is to be further understood that for anyparticular subject, specific dosage regimens should be adjusted overtime according to the individual need and the professional judgment ofthe person administering or supervising the administration of thecompositions, and that the concentration ranges set forth herein areexemplary only and are not intended to limit the scope or practice ofthe claimed compositions.

[1612] If oral administration is desired, the compound should beprovided in a composition that protects it from the acidic environmentof the stomach. For example, the composition can be formulated in anenteric coating that maintains its integrity in the stomach and releasesthe active compound in the intestine. The composition may also beformulated in combination with an antacid or other such ingredient.

[1613] Oral compositions will generally include an inert diluent or anedible carrier and may be compressed into tablets or enclosed in gelatincapsules. For the purpose of oral therapeutic administration, the activecompound or compounds can be incorporated with excipients and used inthe form of tablets, capsules, or troches. Pharmaceutically compatiblebinding agents and adjuvant materials can be included as part of thecomposition.

[1614] The tablets, pills, capsules, troches, and the like can containany of the following ingredients or compounds of a similar nature: abinder such as, but not limited to, gum tragacanth, acacia, corn starch,or gelatin; an excipient such as microcrystalline cellulose, starch, orlactose; a disintegrating agent such as, but not limited to, alginicacid and corn starch; a lubricant such as, but not limited to, magnesiumstearate; a gildant, such as, but not limited to, colloidal silicondioxide; a sweetening agent such as sucrose or saccharin; and aflavoring agent such as peppermint, methyl salicylate, or fruitflavoring.

[1615] When the dosage unit form is a capsule, it can contain, inaddition to material of the above type, a liquid carrier such as a fattyoil. In addition, dosage unit forms can contain various other materials,which modify the physical form of the dosage unit, for example, coatingsof sugar and other enteric agents. The compounds can also beadministered as a component of an elixir, suspension, syrup, wafer,chewing gum or the like. A syrup may contain, in addition to the activecompounds, sucrose as a sweetening agent and certain preservatives, dyesand colorings, and flavors.

[1616] The active materials can also be mixed with other activematerials that do not impair the desired action, or with materials thatsupplement the desired action.

[1617] Solutions or suspensions used for parenteral, intradermal,subcutaneous, or topical application can include any of the followingcomponents: a sterile diluent such as water for injection, salinesolution, fixed oil, a naturally occurring vegetable oil such as sesameoil, coconut oil, peanut oil, cottonseed oil, and the like, or asynthetic fatty vehicle such as ethyl oleate, and the like, polyethyleneglycol, glycerine, propylene glycol, or other synthetic solvent;antimicrobial agents such as benzyl alcohol and methyl parabens;antioxidants such as ascorbic acid and sodium bisulfite; chelatingagents such as ethylenediaminetetraacetic acid (EDTA); buffers such asacetates, citrates, and phosphates; and agents for the adjustment oftonicity such as sodium chloride and dextrose. Parenteral preparationscan be enclosed in ampoules, disposable syringes, or multiple dose vialsmade of glass, plastic, or other suitable material. Buffers,preservatives, antioxidants, and the like can be incorporated asrequired.

[1618] Where administered intravenously, suitable carriers includephysiological saline, phosphate buffered saline (PBS), and solutionscontaining thickening and solubilizing agents such as glucose,polyethylene glycol, polypropyleneglycol, and mixtures thereof.Liposomal suspensions including tissue-targeted liposomes may also besuitable as pharmaceutically acceptable carriers. These may be preparedaccording to methods known for example, as described in U.S. Pat. No.4,522,811.

[1619] The active compounds may be prepared with carriers that protectthe compound against rapid elimination from the body, such astime-release formulations or coatings. Such carriers include controlledrelease formulations, such as, but not limited to, implants andmicroencapsulated delivery systems, and biodegradable, biocompatiblepolymers such as collagen, ethylene vinyl acetate, polyanhydrides,polyglycolic acid, polyorthoesters, polylactic acid, and the like.Methods for preparation of such formulations are known to those skilledin the art.

[1620] The compounds of the invention can be administered orally,parenterally (IV, IM, depo-IM, SQ, and depo-SQ), sublingually,intranasally (inhalation), intrathecally, topically, or rectally. Dosageforms known to those skilled in the art are suitable for delivery of thecompounds of the invention.

[1621] Compounds of the invention may be administered enterally orparenterally. When administered orally, compounds of the invention canbe administered in usual dosage forms for oral administration as is wellknown to those skilled in the art. These dosage forms include the usualsolid unit dosage forms of tablets and capsules as well as liquid dosageforms such as solutions, suspensions, and elixirs. When the solid dosageforms are used, it is preferred that they be of the sustained releasetype so that the compounds of the invention need to be administered onlyonce or twice daily.

[1622] The oral dosage forms are administered to the patient 1, 2, 3, or4 times daily. It is preferred that the compounds of the invention beadministered either three or fewer times, more preferably once or twicedaily. Hence, it is preferred that the compounds of the invention beadministered in oral dosage form. It is preferred that whatever oraldosage form is used, that it be designed so as to protect the compoundsof the invention from the acidic environment of the stomach. Entericcoated tablets are well known to those skilled in the art. In addition,capsules filled with small spheres each coated to protect from theacidic stomach, are also well known to those skilled in the art.

[1623] When administered orally, an administered amount therapeuticallyeffective to inhibit beta-secretase activity, to inhibit A betaproduction, to inhibit A beta deposition, or to treat or prevent AD isfrom about 0.1 mg/day to about 1,000 mg/day. It is preferred that theoral dosage is from about 1 mg/day to about 100 mg/day. It is morepreferred that the oral dosage is from about 5 mg/day to about 50mg/day. It is understood that while a patient may be started at onedose, that dose may be varied over time as the patient's conditionchanges.

[1624] Compounds of the invention may also be advantageously deliveredin a nano crystal dispersion formulation. Preparation of suchformulations is described, for example, in U.S. Pat. No. 5,145,684. Nanocrystalline dispersions of HIV protease inhibitors and their method ofuse are described in U.S. Pat. No. 6,045,829. The nano crystallineformulations typically afford greater bioavailability of drug compounds.

[1625] The compounds of the invention can be used in combination, witheach other or with other therapeutic agents or approaches used to treator prevent the conditions listed above. Such agents or approachesinclude: acetylcholine esterase inhibitors such as tacrine(tetrahydroaminoacridine, marketed as COGNEX®), donepezil hydrochloride,(marketed as Aricept® and rivastigmine (marketed as Exelon®);gamma-secretase inhibitors; anti-inflammatory agents such ascyclooxygenase II inhibitors; anti-oxidants such as Vitamin E andginkolides; immunological approaches, such as, for example, immunizationwith A beta peptide or administration of anti-A beta peptide antibodies;statins; and direct or indirect neurotropic agents such asCerebrolysin®, AIT-082 (Emilieu, 2000, Arch. Neurol. 57:454), and otherneurotropic agents of the future.

[1626] It should be apparent to one skilled in the art that the exactdosage and frequency of administration will depend on the particularcompounds of the invention administered, the particular condition beingtreated, the severity of the condition being treated, the age, weight,general physical condition of the particular patient, and othermedication the individual may be taking as is well known toadministering physicians who are skilled in this art.

[1627] The invention may be further understood with reference to thefollowing biological examples. These examples are intended to berepresentative of specific embodiments of the invention, and are notintended as limiting the scope of the invention.

BIOLOGY EXAMPLES Biology Example A

[1628] Enzyme Inhibition Assay

[1629] The compounds of the invention are analyzed for inhibitoryactivity by use of the MBP-C125 assay. This assay determines therelative inhibition of beta-secretase cleavage of a model APP substrate,MBP-C125SW, by the compounds assayed as compared with an untreatedcontrol. A detailed description of the assay parameters can be found,for example, in U.S. Pat. No. 5,942,400. Briefly, the substrate is afusion peptide formed of maltose binding protein (MBP) and the carboxyterminal 125 amino acids of APP-SW, the Swedish mutation. Thebeta-secretase enzyme is derived from human brain tissue as described inSinha et al, 1999, Nature 40:537-540) or recombinantly produced as thefull-length enzyme (amino acids 1-501), and can be prepared, forexample, from 293 cells expressing the recombinant cDNA, as described inWO00/47618.

[1630] Inhibition of the enzyme is analyzed, for example, by immunoassayof the enzyme's cleavage products. One exemplary ELISA uses an anti-MBPcapture antibody that is deposited on precoated and blocked 96-well highbinding plates, followed by incubation with diluted enzyme reactionsupernatant, incubation with a specific reporter antibody, for example,biotinylated anti-SW192 reporter antibody, and further incubation withstreptavidin/alkaline phosphatase. In the assay, cleavage of the intactMBP-C125SW fusion protein results in the generation of a truncatedamino-terminal fragment, exposing a new SW-192 antibody-positive epitopeat the carboxy terminus. Detection is effected by a fluorescentsubstrate signal on cleavage by the phosphatase. ELISA only detectscleavage following Leu 596 at the substrate's APP-SW 751 mutation site.

[1631] Specific Assay Procedure:

[1632] Compounds are diluted in a 1:1 dilution series to a six-pointconcentration curve (two wells per concentration) in one 96-plate rowper compound tested. Each of the test compounds is prepared in DMSO tomake up a 10 millimolar stock solution. The stock solution is seriallydiluted in DMSO to obtain a final compound concentration of 200micromolar at the high point of a 6-point dilution curve. Ten (10)microliters of each dilution is added to each of two wells on row C of acorresponding V-bottom plate to which 190 microliters of 52 millimolarNaOAc, 7.9% DMSO, pH 4.5 are pre-added. The NaOAc diluted compound plateis spun down to pellet precipitant and 20 microliters/well istransferred to a corresponding flat-bottom plate to which 30 microlitersof ice-cold enzyme-substrate mixture (2.5 microliters MBP-C125SWsubstrate, 0.03 microliters enzyme and 24.5 microliters ice cold 0.09%TX100 per 30 microliters) is added. The final reaction mixture of 200micromolar compound at the highest curve point is in 5% DMSO, 20millimolar NaOAc, 0.06% TX100, at pH 4.5.

[1633] Warming the plates to 37 degrees C. starts the enzyme reaction.After 90 minutes at 37 degrees C., 200 microliters/well cold specimendiluent is added to stop the reaction and 20 microliters/well wastransferred to a corresponding anti-MBP antibody coated ELISA plate forcapture, containing 80 microliters/well specimen diluent. This reactionis incubated overnight at 4 degrees C. and the ELISA is developed thenext day after a 2 hour incubation with anti-192SW antibody, followed byStreptavidin-AP conjugate and fluorescent substrate. The signal is readon a fluorescent plate reader.

[1634] Relative compound inhibition potency is determined by calculatingthe concentration of compound that showed a fifty percent reduction indetected signal (IC₅₀) compared to the enzyme reaction signal in thecontrol wells with no added compound. In this assay, the compounds ofthe invention exhibited an IC₅₀ of less than 50 micromolar.

Biology Example B

[1635] Cell Free Inhibition Assay Utilizing a Synthetic APP Substrate

[1636] A synthetic APP substrate that can be cleaved by beta-secretaseand having N-terminal biotin and made fluorescent by the covalentattachment of Oregon green at the Cys residue is used to assaybeta-secretase activity in the presence or absence of the inhibitorycompounds of the invention. Useful substrates include the following:

[1637] Biotin-SEVNL-DAEFR[Oregon green]KK [SEQ ID NO: 1]

[1638] Biotin-SEVKM-DAEFR[Oregon green]KK [SEQ ID NO: 2]

[1639] Biotin-GLNIKTEEISEISY-EVEFRC[Oregon green]KK [SEQ ID NO: 3]

[1640] Biotin-ADRGLTTRPGSGLTNIKTEEISEVNL-DAEF[Oregon green]KK [SEQ IDNO: 4]

[1641] Biotin-FVNQHLCoxGSHLVEALY-LVCoxGERGFFYTPKA[Oregon green]KK [SEQID NO: 5]

[1642] The enzyme (0.1 nanomolar) and test compounds (0.001-100micromolar) are incubated in pre-blocked, low affinity, black plates(384 well) at 37 degrees for 30 minutes. The reaction is initiated byaddition of 150 millimolar substrate to a final volume of 30 microliterper well. The final assay conditions are: 0.001-100 micromolar compoundinhibitor; 0.1 molar sodium acetate (pH 4.5); 150 nanomolar substrate;0.1 nanomolar soluble beta-secretase; 0.001% Tween 20, and 2% DMSO. Theassay mixture is incubated for 3 hours at 37 degrees C., and thereaction is terminated by the addition of a saturating concentration ofimmunopure streptavidin. After incubation with streptavidin at roomtemperature for 15 minutes, fluorescence polarization is measured, forexample, using a LJL Acqurest (Ex485 nm/Em530 nm). The activity of thebeta-secretase enzyme is detected by changes in the fluorescencepolarization that occur when the substrate is cleaved by the enzyme.Incubation in the presence or absence of compound inhibitor demonstratesspecific inhibition of beta-secretase enzymatic cleavage of itssynthetic APP substrate. In this assay, compounds of the inventionexhibited an IC₅₀ of less than 50 micromolar.

Biology Example C

[1643] Beta-Secretase Inhibition: P26-P4′SW Assay

[1644] Synthetic substrates containing the beta-secretase cleavage siteof APP are used to assay beta-secretase activity, using the methodsdescribed, for example, in published PCT application WO00/47618. TheP26-P4′SW substrate is a peptide of the sequence:

[1645] (biotin)CGGADRGLTTRPGSGLTNIKTEEISEVNLDAEF [SEQ ID NO: 6]

[1646] The P26-P1 standard has the sequence:

[1647] (biotin)CGGADRGLTTRPGSGLTNIKTEEISEVNL [SEQ ID NO: 7].

[1648] Briefly, the biotin-coupled synthetic substrates are incubated ata concentration of from about 0 to about 200 micromolar in this assay.When testing inhibitory compounds, a substrate concentration of about1.0 micromolar is preferred. Test compounds diluted in DMSO are added tothe reaction mixture, with a final DMSO concentration of 5%. Controlsalso contain a final DMSO concentration of 5%. The concentration of betasecretase enzyme in the reaction is varied, to give productconcentrations with the linear range of the ELISA assay, about 125 to2000 picomolar, after dilution.

[1649] The reaction mixture also includes 20 millimolar sodium acetate,pH 4.5, 0.06% Triton X100, and is incubated at 37 degrees C. for about 1to 3 hours. Samples are then diluted in assay buffer (for example, 145.4nanomolar sodium chloride, 9.51 millimolar sodium phosphate, 7.7millimolar sodium azide, 0.05% Triton X405, 6 g/liter bovine serumalbumin, pH 7.4) to quench the reaction, then diluted further forimmunoassay of the cleavage products.

[1650] Cleavage products can be assayed by ELISA. Diluted samples andstandards are incubated in assay plates coated with capture antibody,for example, SW192, for about 24 hours at 4 degrees C. After washing inTTBS buffer (150 millimolar sodium chloride, 25 millimolar Tris, 0.05%Tween 20, pH 7.5), the samples are incubated with streptavidin-APaccording to the manufacturer's instructions. After a one hourincubation at room temperature, the samples are washed in TTBS andincubated with fluorescent substrate solution A (31.2 g/liter2-amino-2-methyl-1-propanol, 30 mg/liter, pH 9.5). Reaction withstreptavidin-alkaline phosphate permits detection by fluorescence.Compounds that are effective inhibitors of beta-secretase activitydemonstrate reduced cleavage of the substrate as compared to a control.

Biology Example D

[1651] Assays Using Synthetic Oligopeptide-Substrates

[1652] Synthetic oligopeptides are prepared that incorporate the knowncleavage site of beta-secretase, and optionally detectable tags, such asfluorescent or chromogenic moieties. Examples of such peptides, as wellas their production and detection methods are described in U.S. Pat. No:5,942,400, herein incorporated by reference. Cleavage products can bedetected using high performance liquid chromatography, or fluorescent orchromogenic detection methods appropriate to the peptide to be detected,according to methods well known in the art.

[1653] By way of example, one such peptide has the sequence SEVNL-DAEF[SEQ ID NO: 8], and the cleavage site is between residues 5 and 6.Another preferred substrate has the sequenceADRGLTTRPGSGLTNIKTEEISEVNL-DAEF [SEQ ID NO: 9], and the cleavage site isbetween residues 26 and 27.

[1654] These synthetic APP substrates are incubated in the presence ofbeta-secretase under conditions sufficient to result in beta-secretasemediated cleavage of the substrate. Comparison of the cleavage resultsin the presence of the compound inhibitor to control results provides ameasure of the compound's inhibitory activity.

Biology Example E

[1655] Inhibition of Beta-Secretase Activity—Cellular Assay

[1656] An exemplary assay for the analysis of inhibition ofbeta-secretase activity utilizes the human embryonic kidney cell lineHEKp293 (ATCC Accession No. CRL-1573) transfected with APP751 containingthe naturally occurring double mutation Lys651Met52 to Asn651Leu652(numbered for APP751), commonly called the Swedish mutation and shown tooverproduce A beta (Citron et al., 1992, Nature 360:672-674), asdescribed in U.S. Pat. No. 5,604,102.

[1657] The cells are incubated in the presence/absence of the inhibitorycompound (diluted in DMSO) at the desired concentration, generally up to10 micrograms/ml. At the end of the treatment period, conditioned mediais analyzed for beta-secretase activity, for example, by analysis ofcleavage fragments. A beta can be analyzed by immunoassay, usingspecific detection antibodies. The enzymatic activity is measured in thepresence and absence of the compound inhibitors to demonstrate specificinhibition of beta-secretase mediated cleavage of APP substrate.

Biology Example F

[1658] Inhibition of Beta-Secretase in Animal Models of AD

[1659] Various animal models can be used to screen for inhibition ofbeta-secretase activity. Examples of animal models useful in theinvention include, but are not limited to, mouse, guinea pig, dog, andthe like. The animals used can be wild type, transgenic, or knockoutmodels. In addition, mammalian models can express mutations in APP, suchas APP695-SW and the like described herein. Examples of transgenicnon-human mammalian models are described in U.S. Pat. Nos. 5,604,102,5,912,410 and 5,811,633.

[1660] PDAPP mice, prepared as described in Games et al., 1995, Nature373:523-527 are useful to analyze in vivo suppression of A beta releasein the presence of putative inhibitory compounds. As described in U.S.Pat. No. 6,191,166, 4 month old PDAPP mice are administered compoundformulated in vehicle, such as corn oil. The mice are dosed withcompound (1-30 mg/ml; preferably 1-10 mg/ml). After time, e.g., 3-10hours, the animals are sacrificed, and brains removed for analysis.

[1661] Transgenic animals are administered an amount of the compoundinhibitor formulated in a carrier suitable for the chosen mode ofadministration. Control animals are untreated, treated with vehicle, ortreated with an inactive compound. Administration can be acute, i.e.,single dose or multiple doses in one day, or can be chronic, i.e.,dosing is repeated daily for a period of days. Beginning at time 0,brain tissue or cerebral fluid is obtained from selected animals andanalyzed for the presence of APP cleavage peptides, including A beta,for example, by immunoassay using specific antibodies for A betadetection. At the end of the test period, animals are sacrificed andbrain tissue or cerebral fluid is analyzed for the presence of A betaand/or beta-amyloid plaques. The tissue is also analyzed for necrosis.

[1662] Animals administered the compound inhibitors of the invention areexpected to demonstrate reduced A beta in brain tissues or cerebralfluids and reduced beta amyloid plaques in brain tissue, as comparedwith non-treated controls.

Biology Example G

[1663] Inhibition of A Beta Production in Human Patients

[1664] Patients suffering from Alzheimer's Disease (AD) demonstrate anincreased amount of A beta in the brain. AD patients are administered anamount of the compound inhibitor formulated in a carrier suitable forthe chosen mode of administration. Administration is repeated daily forthe duration of the test period. Beginning on day 0, cognitive andmemory tests are performed, for example, once per month.

[1665] Patients administered the compound inhibitors are expected todemonstrate slowing or stabilization of disease progression as analyzedby changes in one or more of the following disease parameters: A betapresent in CSF or plasma; brain or hippocampal volume; A beta depositsin the brain; amyloid plaque in the brain; and scores for cognitive andmemory function, as compared with control, non-treated patients.

Biology Example H

[1666] Prevention of A Beta Production in Patients at Risk for AD

[1667] Patients predisposed or at risk for developing AD are identifiedeither by recognition of a familial inheritance pattern, for example,presence of the Swedish Mutation, and/or by monitoring diagnosticparameters. Patients identified as predisposed or at risk for developingAD are administered an amount of the compound inhibitor formulated in acarrier suitable for the chosen mode of administration. Administrationis repeated daily for the duration of the test period. Beginning on day0, cognitive and memory tests are performed, for example, once permonth.

[1668] Patients administered the compound inhibitors are expected todemonstrate slowing or stabilization of disease progression as analyzedby changes in one or more of the following disease parameters: A betapresent in CSF or plasma; brain or hippocampal volume; amyloid plaque inthe brain; and scores for cognitive and memory function, as comparedwith control, non-treated patients.

[1669] It should be noted that, as used in this specification and theappended claims, the singular forms “a,” “an,” and “the” include pluralreferents unless the content clearly dictates otherwise. Thus, forexample, reference to a composition containing “a compound” includes amixture of two or more compounds. It should also be noted that the term“or” is generally employed in its sense including “and/or” unless thecontent clearly dictates otherwise.

[1670] Unless defined otherwise, all scientific and technical terms usedherein have the same meaning as commonly understood by one of skill inthe art to which this invention belongs.

[1671] All patents and publications referred to herein are herebyincorporated by reference for all purposes.

[1672] The invention has been described with reference to variousspecific and preferred embodiments and techniques. However, it should beunderstood that many variations and modifications may be made whileremaining within the spirit and scope of the invention.

What is claimed is:
 1. A compound of the formula II:

or a pharmaceutically acceptable salt thereof, where Rc is (I) —C₁-C₁₀alkyl optionally substituted with one, two or three groups independentlyselected from the group consisting of C₁-C₃ alkyl, halogen, —OH, —SH,—C≡N, —CF₃, C₁-C₆ alkoxy, —O-phenyl, —NR_(1-a)R_(1-b), —OC═ONR_(1-a)R_(1-b), —S(═O)₀₋₂ R_(1-a), —NR_(1-a)C═O NR_(1-a)R_(1-b), —C═ONR_(1-a)R_(1-b), and —S(═O)₂ NR_(1-a)R_(1-b) wherein R_(1-a) and R_(1-b)at each occurrence are independently H or C₁-C₆ alkyl, (II)—(CH₂)₀₋₃—(C₃-C₈) cycloalkyl where cycloalkyl can be optionallysubstituted with one, two or three substituents independently selectedfrom the group consisting of C₁-C₃ alkyl, halogen, —OH, —SH, —C≡N, —CF₃,C₁-C₆ alkoxy, —O-phenyl, —CO₂H, —CO₂—(C₁-C₄ alkyl), and —NR_(1-a)R_(1-b)(III) —(CR_(C-x)R_(C-y))₀₋₄—R_(C-aryl) where R_(C-x) and R_(C-y) areindependently selected from the group consisting of —H, C₁-C₄ alkyloptionally substituted with 1 or 2 —OH, C₁-C₄ alkoxy optionallysubstituted with 1, 2, or 3 halogen, —(CH₂)₀₋₄—C₃-C₈ cycloalkyl, C₂-C₆alkenyl containing one or two double bonds, C₂-C₆ alkynyl containing oneor two triple bonds, and phenyl, or R_(C-x) and R_(C-y) are takentogether with the carbon to which they are attached to form a carbocycleof three, four, five, six or seven carbon atoms, where one carbon atomis optionally replaced by a group selected from —O—, —S—, —SO₂—,—NR_(N-2)— and R_(C-aryl), wherein R_(C-aryl) is phenyl, which isoptionally substituted with 1, 2, or 3 groups that are independently:(1) C₁-C₆ alkyl, optionally substituted with one, two or threesubstituents selected from the group consisting of C₁-C₃ alkyl, halogen,—OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b), (2) —OH, (3)—NO₂, (4) halogen, (5) —CO₂H, (6) —C≡N, (7) —(CH₂)₀₋₄—CO—NR_(N-2)R_(N-3)where R_(N-2) and R_(N-3) are independently selected from the groupconsisting of: (a) —H, (b) —C₁-C₆ alkyl optionally substituted with onesubstituent selected from the group consisting of: (i) —OH, and (ii)—NH₂, (c) —C₁-C₆ alkyl optionally substituted with 1, 2, or 3 groupsthat are independently —F, —Cl, —Br, —I, or OH, (d) —C₃-C₇ cycloalkyl,(e) —(C₁-C₂ alkyl)-(C₃-C₇ cycloalkyl), (f) —(C₁-C₆ alkyl)-O—(C₁-C₃alkyl), (g) —C₂-C₆ alkenyl (h) —C₂-C₆ alkynyl (i) —C₁-C₆ alkyl chainwith one double bond and one triple bond, (j) —R_(1-aryl) whereinR_(1-aryl) at each occurrence is independently phenyl, naphthyl,indanyl, indenyl, dihydronaphthyl, or tetralinyl each of which isoptionally substituted with 1, 2, 3, or 4 groups that are independently:(i) C₁-C₆ alkyl optionally substituted with one, two or threesubstituents independently selected from the group consisting of C₁-C₃alkyl, —F, —Cl, —Br, —I, —OH, —SH, —NR_(1-a)R_(1-b), —C═N, —CF₃, andC₁-C₃ alkoxy, (ii) C₂-C₆ alkenyl with one or two double bonds,optionally substituted with one, two or three substituents independentlyselected from the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃,C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b), (iii) C₂-C₆ alkynyl optionallysubstituted with 1, 2, or 3 groups that are independently selected fromthe group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and—NR_(1-a)R_(1-b), (iv) —F, Cl, —Br and —I, (v) —C₁-C₆ alkoxy optionallysubstituted with 1, 2, or 3 —F, (vi) —NR_(N-2)R_(N-3), (vii) —OH, (viii)—C≡N, (ix) C₃-C₇ cycloalkyl, optionally substituted with 1, 2, or 3groups that are selected from the group consisting of —F, —Cl, —OH, —SH,—C≡N, —CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b), (x) —CO—(C₁-C₄ alkyl),(xi) —SO₂—NR_(1-a)R_(1-b), (xii) —CO—NR_(1-a)R_(1-b), or (xiii)—SO₂—(C₁-C₄ alkyl), (k) —R_(1-heteroaryl) wherein R_(1-heteroaryl) ateach occurrence is independently selected from the group consisting ofpyridinyl, pyrimidinyl, quinolinyl, benzothienyl, indolyl, indolinyl,pryidazinyl, pyrazinyl, isoindolyl, isoquinolyl, quinazolinyl,quinoxalinyl, phthalazinyl, imidazolyl, isoxazolyl, pyrazolyl, oxazolyl,thiazolyl, indolizinyl, indazolyl, benzothiazolyl, benzimidazolyl,benzofuranyl, furanyl, thienyl, pyrrolyl, oxadiazolyl, thiadiazolyl,triazolyl, tetrazolyl, oxazolopyridinyl, imidazopyridinyl, isothiazolyl,naphthyridinyl, cinnolinyl, carbazolyl, beta-carbolinyl, isochromanyl,chromanyl, tetrahydroisoquinolinyl, isoindolinyl,isobenzotetrahydrofuranyl, isobenzotetrahydrothienyl, isobenzothienyl,benzoxazolyl, pyridopyridinyl, benzotetrahydrofuranyl,benzotetrahydrothienyl, purinyl, benzodioxolyl, triazinyl, phenoxazinyl,phenothiazinyl, pteridinyl, benzothiazolyl, imidazopyridinyl,imidazothiazolyl, dihydrobenzisoxazinyl, benzisoxazinyl, benzoxazinyl,dihydrobenzisothiazinyl, benzopyranyl, benzothiopyranyl, coumarinyl,isocoumarinyl, chromonyl, chromanonyl, pyridinyl-N-oxide,tetrahydroquinolinyl, dihydroquinolinyl, dihydroquinolinonyl,dihydroisoquinolinonyl, dihydrocoumarinyl, dihydroisocoumarinyl,isoindolinonyl, benzodioxanyl, benzoxazolinonyl, pyrrolyl N-oxide,pyrimidinyl N-oxide, pyridazinyl N-oxide, pyrazinyl N-oxide, quinolinylN-oxide, indolyl N-oxide, indolinyl N-oxide, isoquinolyl N-oxide,quinazolinyl N-oxide, quinoxalinyl N-oxide, phthalazinyl N-oxide,imidazolyl N-oxide, isoxazolyl N-oxide, oxazolyl N-oxide, thiazolylN-oxide, indolizinyl N-oxide, indazolyl N-oxide, benzothiazolyl N-oxide,benzimidazolyl N-oxide, pyrrolyl N-oxide, oxadiazolyl N-oxide,thiadiazolyl N-oxide, triazolyl N-oxide, tetrazolyl N-oxide,benzothiopyranyl S-oxide, and benzothiopyranyl S,S-dioxide, where theR_(1-heteroaryl) group is optionally substituted with 1, 2, 3, or 4groups that are independently: (i) C₁-C₆ alkyl optionally substitutedwith 1, 2, or 3 groups independently selected from the group consistingof C₁-C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH, —NR_(1-a)R_(1-b), —C≡N,—CF₃, and C₁-C₃ alkoxy, (ii) C₂-C₆ alkenyl optionally substituted with1, 2, or 3 groups that are independently —F, —Cl, —OH, —SH, —C≡N, —CF₃,C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b), (iii) C₂-C₆ alkynyl optionallysubstituted with 1, 2, or 3 groups that are independently selected fromthe group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and—NR_(1-a)R_(1-b), (iv) —F, —Cl, —Br and —I, (v) —C₁-C₆ alkoxy optionallysubstituted with one, two, or three —F, (vi) —(CH₂)₀₋₄—NR_(N-2)R_(N-3),(vii) —OH, (viii) —C≡N, (ix) (CH₂)₀₋₄—C₃-C₇ cycloalkyl, optionallysubstituted with 1, 2, or 3 groups that are independently selected fromthe group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and—NR_(1-a)R_(1-b), (x) (CH₂)₀₋₄—CO—(C₁-C₆ alkyl), (xi)(CH₂)₀₋₄—SO₂—NR_(N-2)R_(N-3), (xii) (CH₂)₀₋₄—CO—NR_(N-2)R_(N-3), (xiii)(CH₂)₀₋₄—SO₂—(C₁-C₆ alkyl), (xiv) (CH₂)₀₋₄—N(R_(N-2))—SO₂—, and (xv)(CH₂)₀₋₄—N(R_(N-2))—C(O)—, (8) —(CH₂)₀₋₄—CO—(C₁-C₁₂ alkyl), (9)—(CH₂)₀₋₄—CO—(C₂-C₁₂ alkenyl), (10) —(CH₂)₀₋₄—CO—(C₂-C₁₂ alkynyl), (11)—(CH₂)₀₋₄—CO—(CH₂)₀₋₄(C₃-C₇ cycloalkyl), (12) —(CH₂)₀₋₄—CO—R_(1-aryl),(13) —(CH₂)₀₋₄—CO—R_(1-heteroaryl), (14) —(CH₂)₀₋₄—CO—R_(1-heterocycle)wherein R_(1-heterocycle) at each occurrence is independently selectedfrom the group consisting of morpholinyl, thiomorpholinyl,thiomorpholinyl S-oxide, thiomorpholinyl S,S-dioxide, piperazinyl,homopiperazinyl, pyrrolidinyl, pyrrolinyl, tetrahydropyranyl,piperidinyl, tetrahydrofuranyl, tetrahydrothienyl, homopiperidinyl,homomorpholinyl, homothiomorpholinyl, homothiomorpholinyl S,S-dioxide,oxazolidinonyl, dihydropyrazolyl, dihydropyrrolyl, dihydropyrazinyl,dihydropyridinyl, dihydropyrimidinyl, dihydrofuryl, dihydropyranyl,tetrahydrothienyl S-oxide, tetrahydrothienyl S,S-dioxide, andhomothiomorpholinyl S-oxide, where the R_(1-heterocycle) group is bondedby any atom of the parent R_(1-heterocycle) group substituted byhydrogen such that the new bond to the R_(1-heterocycle) group replacesthe hydrogen atom and its bond, where heterocycle is optionallysubstituted with 1, 2, 3, or 4 groups that are independently: (a) C₁-C₆alkyl optionally substituted with one, two or three substituentsindependently selected from the group consisting of C₁-C₃ alkyl,halogen, —OH, —SH, —NR_(1-a)R_(1-b) —C≡N, —CF₃, and C₁-C₃ alkoxy, (b)C₂-C₆ alkenyl with one or two double bonds, optionally substituted withone, two or three substituents independently selected from the groupconsisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and—NR_(1-a)R_(1-b) (c) C₂-C₆ alkynyl with one or two triple bonds,optionally substituted with one, two or three substituents independentlyselected from the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃,C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b) (d) halogen, (e) C₁-C₆ alkoxy, (f)—C₁-C₆ alkoxy optionally substituted with one, two, or three —F, (g)—NR_(N-2)R_(N-3), (h) —OH, (i) —C≡N, (j) (CH₂)₀₋₄—(C₃-C₇ cycloalkyl),optionally substituted with 1, 2, or 3 groups independently selectedfrom the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃alkoxy, and —NR_(1-a)R_(1-b), (k) —(CH₂)₀₋₄—CO—(C₁-C₄ alkyl), (l)—(CH₂)₀₋₄—SO₂—NR_(1-a)R_(1-b), (m) —(CH₂)₀₋₄—CO—NR_(1-a)R_(1-b), (n)—(CH₂)₀₋₄—SO₂—(C₁-C₆ alkyl), and (o) ═O, (p) —(CH₂)₀₋₄—N(R_(N-2))—SO₂—(q) —(CH₂)₀₋₄—N(R_(N-2))—C(O)— (15) —(CH₂)₀₋₄—CO—R_(N-4) wherein R_(N-4)at each occurrence is independently selected from the group consistingof morpholinyl, thiomorpholinyl, pyrrolidinonyl, pyrrolyl, pyrazolyl,thienyl, pyridyl N-oxide, piperazinyl, piperidinyl, homomorpholinyl,homothiomorpholinyl, homothiomorpholinyl S-oxide, homothiomorpholinylS,S-dioxide, pyrrolinyl and pyrrolidinyl where each group is optionallysubstituted with 1, 2, 3, or 4 groups that are independently C₁-C₆alkyl, (16) —(CH₂)₀₋₄—CO₂—R_(N-5) where R_(N-5) at each occurrence isindependently selected from the group consisting of: (a) C₁-C₆ alkyl,(b) —(CH₂)₀₋₂—(R_(1-aryl)) (c) C₂-C₆ alkenyl, (d) C₂-C₆ alkynyl, (e)C₃-C₇ cycloalkyl, and (f) —(CH₂)₀₋₄—(R_(1-heteroaryl)) (17)—(CH₂)₀₋₄—SO₂—NR_(N-2)R_(N-3) (18) —(CH₂)₀₋₄—SO—(C₁-C₈ alkyl), (19)—(CH₂)₀₋₄—SO₂—(C₁-C₁₂ alkyl), (20) —(CH₂)₀₋₄—SO₂—(C₃-C₇ cycloalkyl),(21) —(CH₂)₀₋₄—N(H or R_(N-5))—CO₂—R_(N-5), (22) —(CH₂)₀₋₄—N(H orR_(N-5))—CO—N(R_(N-5))₂, (23) —(CH₂)₀₋₄—N—CS—N (R_(N-5))₂, (24)—(CH₂)₀₋₄—N(—H or R_(N-5))—CO—R_(N-2), (25) —(CH₂)₀₋₄—NR_(N-2)R_(N-3),(26) —(CH₂)₀₋₄—R_(N-4), (27) —(CH₂)₀₋₄—O—CO—(C₁-C₆ alkyl) (28)—(CH₂)₀₋₄—O—P(O)—(OR₁₀₀)₂ where R₁₀₀ is independently H or C₁-C₄ alkyl,(29) —(CH₂)₀₋₄—O—CO—N (R_(N-5))₂, (30) —(CH₂)₀₋₄—O—CS—N(R_(N-5))₂, (31)—(CH₂)₀₋₄—O—(R_(N-5)), (32) —(CH₂)₀₋₄—O—(R_(N-5))—COOH, (33)—(CH₂)₀₋₄—S—(R_(N-5)), (34) —(CH₂)₀₋₄—O—(C₁-C₆ alkyl) wherein the alkylgroup is optionally substituted with one, two, three, four, or fivesubstituents independently selected from the group consisting of F, Cl,Br, and I, (35) —(CH₂)₀₋₄—(C₃-C₈ cycloalkyl) (36) C₂-C₆ alkenyloptionally substituted with C₁-C₃ alkyl, halogen, —OH, —SH, —C≡N, —CF₃,C₁-C₃ alkoxy, or —NR_(1-a)R_(1-b), (37) C₂-C₆ alkynyl optionallysubstituted with C₁-C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃,C₁-C₃ alkoxy, or —NR_(1-a)R_(1-b), and (38) —(CH₂)₀₋₄—N(—H orR_(N-5))—SO₂—R_(N-2); (IV) —(CR_(C-x)R_(C-y))₀₋₄—R_(C-heteroaryl)wherein R_(C-heteroaryl) at each occurrence is independently selectedfrom the group consisting of pyridinyl, pyrimidinyl, quinolinyl,benzothienyl, indolyl, indolinyl, pryidazinyl, pyrazinyl, isoindolyl,isoquinolyl, quinazolinyl, quinoxalinyl, phthalazinyl, imidazolyl,isoxazolyl, pyrazolyl, oxazolyl, thiazolyl, indolizinyl, indazolyl,benzoisothiazolyl, benzimidazolyl, benzofuranyl, furanyl, thienyl,pyrrolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl,oxazolopyridinyl, isothiazolyl, naphthyridinyl, cinnolinyl, carbazolyl,beta-carbolinyl, isochromanyl, chromanyl, tetrahydroisoquinolinyl,isoindolinyl, isobenzotetrahydrofuranyl, isobenzotetrahydrothienyl,isobenzothienyl, benzoxazolyl, pyridopyridinyl, benzotetrahydrofuranyl,benzotetrahydrothienyl, purinyl, benzodioxolyl, triazinyl, henoxazinyl,phenothiazinyl, pteridinyl, benzothiazolyl, imidazopyridinyl,imidazothiazolyl, dihydrobenzisoxazinyl, benzisoxazinyl, benzoxazinyl,dihydrobenzisothiazinyl, benzopyranyl, benzothiopyranyl, coumarinyl,isocoumarinyl, chromonyl, chromanonyl, tetrahydroquinolinyl,dihydroquinolinyl, dihydroquinolinonyl,dihydroisoquinolinonyl,dihydrocoumarinyl, dihydroisocoumarinyl,isoindolinonyl, benzodioxanyl, benzoxazolinonyl, imidazopyrazolyl,quinazolinonyl, pyrazopyridyl, benzooxadiazolyl, dihydropyrimidinonyl,dihydrobenzofuranonyl, where the R_(C-heteroaryl) group is bonded by anyatom of the parent R_(C-heteroaryl) group substituted by hydrogen suchthat the new bond to the R_(C-heteroaryl) group replaces the hydrogenatom and its bond, where heteroaryl is optionally substituted 1, 2, 3,or 4 groups that are independently: (1) C₁-C₆ alkyl, optionallysubstituted with 1, 2, or 3 groups independently selected from the groupconsisting of C₁-C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁-C₃alkoxy, and —NR_(1-a)R_(1-b), (2) —OH, (3) —NO₂, (4) —F, —Cl, —Br, —I,(5) —CO—OH, (6) —C≡N, (V) C₂-C₁₀ alkenyl optionally substituted withone, two or three substituents independently selected from the groupconsisting of C₁-C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁-C₆alkoxy, —O-phenyl, and —NR_(1-a)R_(1-b), (VI) C₂-C₁₀ alkynyl optionallysubstituted with one, two or three substituents independently selectedfrom the group consisting of C₁-C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH,—C≡N, —CF₃, C₁-C₆ alkoxy, —O-phenyl, and —NR_(1-a)R_(1-b), (VII) —(C₁-C₆alkyl)-O—(C₁-C₆ alkyl)-OH, (VIII) —CH₂—NH—CH₂—CH(—O—CH₂—CH₃)₂, (IX)—(CH₂)₀₋₆—C (═NR_(1-a)) (NR_(1-a)R_(1-b)) where R_(N) is (I)R_(N-1)—X_(N)— where X_(N) is —CO—, and where R_(N-1) is selected fromthe group consisting of: (A) phenyl, which is optionally substitutedwith one, two or three of the following substituents which can be thesame or different and are: (1) C₁-C₆ alkyl, optionally substituted withone, two or three substituents selected from the group consisting ofC₁-C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C═N, —CF₃, C₁-C₃ alkoxy, and—NR_(1-a)R_(1-b), wherein R_(1-a) and R_(1-b) at each occurrence areindependently H or C₁-C₆ alkyl, (2) —OH, (3) —NO₂, (4) —F, —Cl, —Br, —I,(5) —CO₂H, (6) —C≡N, (7) —(CH₂)₀₋₄—CO—NR_(N-2)R_(N-3) where R_(N-2) andR_(N-3) are the same or different and are selected from the groupconsisting of: (a) —H, (b) —C₁-C₈ alkyl optionally substituted with onesubstituent selected from the group consisting of: (i) —OH, (ii) —NH₂,(iii) phenyl, (c) —C₁-C₈ alkyl optionally substituted with 1, 2, or 3groups that are independently —F, —Cl, —Br, or —I, (d) —C₃-C₈cycloalkyl, (e) —(C₁-C₂ alkyl)-(C₃-C₈ cycloalkyl), (f) —(C₁-C₆alkyl)-O—(C₁-C₃ alkyl) (g) —C₂-C₆ alkenyl, (h) —C₂-C₆ alkynyl, (i)—C₁-C₆ alkyl chain with one double bond and one triple bond, (j)—R_(1-aryl), wherein R_(1-aryl) at each occurrence is independentlyphenyl, naphthyl, indanyl, indenyl, dihydronaphthyl, or tetralinyl eachof which is optionally substituted with 1, 2, 3, or 4 groups that areindependently: (i) C₁-C₆ alkyl optionally substituted with one, two orthree substituents independently selected from the group consisting ofC₁-C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH, —NR_(1-a)R_(1-b), —C≡N, —CF₃,and C₁-C₃ alkoxy, (ii) C₂-C₆ alkenyl with one or two double bonds,optionally substituted with one, two or three substituents independentlyselected from the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃,C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b), (iii) C₂-C₆ alkynyl optionallysubstituted with 1, 2, or 3 groups that are independently selected fromthe group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and—NR_(1-a)R_(1-b), (iv) —F, Cl, —Br and —I, (v) —C₁-C₆ alkoxy optionallysubstituted with 1, 2, or 3 —F, (vi) —NR_(N-2)R_(N-3), (vii) —OH, (viii)—C≡N, (ix) C₃-C₇ cycloalkyl, optionally substituted with 1, 2, or 3groups that are selected from the group consisting of —F, —Cl, —OH, —SH,—C≡N, —CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b), (X) —CO—(C₁-C₄ alkyl),(xi) —SO₂—NR_(1-a)R_(1-b), (xii) —CO—NR_(1-a)R_(1-b), or (xiii)—SO₂—(C₁-C₄ alkyl) (k) —R_(1-heteroaryl) wherein R_(1-heteroaryl) ateach occurrence is independently selected from the group consisting ofpyridinyl, pyrimidinyl, quinolinyl, benzothienyl, indolyl, indolinyl,pryidazinyl, pyrazinyl, isoindolyl, isoquinolyl, quinazolinyl,quinoxalinyl, phthalazinyl, imidazolyl, isoxazolyl, pyrazolyl, oxazolyl,thiazolyl, indolizinyl, indazolyl, benzothiazolyl, benzimidazolyl,benzofuranyl, furanyl, thienyl, pyrrolyl, oxadiazolyl, thiadiazolyl,triazolyl, tetrazolyl, oxazolopyridinyl, imidazopyridinyl, isothiazolyl,naphthyridinyl, cinnolinyl, carbazolyl, beta-carbolinyl, isochromanyl,chromanyl, tetrahydroisoquinolinyl, isoindolinyl,isobenzotetrahydrofuranyl, isobenzotetrahydrothienyl, isobenzothienyl,benzoxazolyl, pyridopyridinyl, benzotetrahydrofuranyl,benzotetrahydrothienyl, purinyl, benzodioxolyl, triazinyl, phenoxazinyl,phenothiazinyl, pteridinyl, benzothiazolyl, imidazopyridinyl,imidazothiazolyl, dihydrobenzisoxazinyl, benzisoxazinyl, benzoxazinyl,dihydrobenzisothiazinyl, benzopyranyl, benzothiopyranyl, coumarinyl,isocoumarinyl, chromonyl, chromanonyl, pyridinyl-N-oxide,tetrahydroquinolinyl, dihydroquinolinyl, dihydroquinolinonyl,dihydroisoquinolinonyl, dihydrocoumarinyl, dihydroisocoumarinyl,isoindolinonyl, benzodioxanyl, benzoxazolinonyl, pyrrolyl N-oxide,pyrimidinyl N-oxide, pyridazinyl N-oxide, pyrazinyl N-oxide, quinolinylN-oxide, indolyl N-oxide, indolinyl N-oxide, isoquinolyl N-oxide,quinazolinyl N-oxide, quinoxalinyl N-oxide, phthalazinyl N-oxide,imidazolyl N-oxide, isoxazolyl N-oxide, oxazolyl N-oxide, thiazolylN-oxide, indolizinyl N-oxide, indazolyl N-oxide, benzothiazolyl N-oxide,benzimidazolyl N-oxide, pyrrolyl N-oxide, oxadiazolyl N-oxide,thiadiazolyl N-oxide, triazolyl N-oxide, tetrazolyl N-oxide,benzothiopyranyl S-oxide, and benzothiopyranyl S,S-dioxide, where theR_(1-heteroaryl) group is optionally substituted with 1, 2, 3, or 4groups that are independently: (i) C₁-C₆ alkyl optionally substitutedwith 1, 2, or 3 groups independently selected from the group consistingof C₁-C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH, —NR_(1-a)R_(1-b), —C≡N,—CF₃, and C₁-C₃ alkoxy, (ii) C₂-C₆ alkenyl optionally substituted with1, 2, or 3 groups that are independently —F, —Cl, —OH, —SH, —C≡N, —CF₃,C₁-C₃ alkoxy, or —NR_(1-a)R_(1-b), (iii) C₂-C₆ alkynyl optionallysubstituted with 1, 2, or 3 groups that are independently —F, —Cl, —OH,—SH, —C≡N, —CF₃, C₁-C₃ alkoxy, or —NR_(1-a)R_(1-b), (iv) —F, —Cl, —Brand —I, (v) —C₁-C₆ alkoxy optionally substituted with one, two, or three—F, (vi) —(CH₂)₀₋₄—NR_(N-2)R_(N-3), (vii) —OH, (viii) —C≡N, (ix)(CH₂)₀₋₄—C₃-C₇ cycloalkyl, optionally substituted with 1, 2, or 3 groupsthat are independently selected from the group consisting of —F, —Cl,—OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b), (x)(CH₂)₀₋₄—CO—(C₁-C₆ alkyl), (xi) (CH₂)₀₋₄—SO₂—NR_(N-2)R_(N-3), (xii)(CH₂)₀₋₄—CO—NR_(N-2)R_(N-3), (xiii) (CH₂)₀₋₄—SO₂—(C₁-C₆ alkyl), (xiv)(CH₂)₀₋₄—N (R_(N-2))—SO₂—, and (xv) (CH₂)₀₋₄—N(R_(N-2))—C(O)—, (l)—R_(1-heterocyle), wherein R_(1-heterocycle) at each occurrence isindependently selected from the group consisting of morpholinyl,thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S,S-dioxide,piperazinyl, homopiperazinyl, pyrrolidinyl, pyrrolinyl,tetrahydropyranyl, piperidinyl, tetrahydrofuranyl, tetrahydrothienyl,homopiperidinyl, homomorpholinyl, homothiomorpholinyl,homothiomorpholinyl S,S-dioxide, oxazolidinonyl, dihydropyrazolyl,dihydropyrrolyl, dihydropyrazinyl, dihydropyridinyl, dihydropyrimidinyl,dihydrofuryl, dihydropyranyl, tetrahydrothienyl S-oxide,tetrahydrothienyl S,S-dioxide, and homothiomorpholinyl S-oxide, wherethe R_(1-heterocycle) group is bonded by any atom of the parentR_(1-heterocycle) group substituted by hydrogen such that the new bondto the R_(1-heterocycle) group replaces the hydrogen atom and its bond,where heterocycle is optionally substituted with 1, 2, 3, or 4 groupsthat are independently: (a) C₁-C₆ alkyl optionally substituted with one,two or three substituents independently selected from the groupconsisting of C₁-C₃ alkyl, halogen, —OH, —SH, —NR_(1-a)R_(1-b) —C≡N,—CF₃, and C₁-C₃ alkoxy, (b) C₂-C₆ alkenyl with one or two double bonds,optionally substituted with one, two or three substituents independentlyselected from the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃,C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b) (c) C₂-C₆ alkynyl with one or twotriple bonds, optionally substituted with one, two or three substituentsindependently selected from the group consisting of —F, —Cl, —OH, —SH,—C≡N, —CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b) (d) halogen, (e) C₁-C₆alkoxy, (f) —C₁-C₆ alkoxy optionally substituted with one, two, or three—F, (g) —NR_(N-2)R_(N-3), (h) —OH, (i) —C≡N, (j) (CH₂)₀₋₄-(C₃-C₈cycloalkyl), optionally substituted with 1, 2, or 3 groups independentlyselected from the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃,C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b), (k) —(CH₂)₀₋₄—CO—(C₁-C₄ alkyl), (l)—(CH₂)₀₋₄—S₂—NR_(1-a)R_(1-b), (m) —(CH₂)₀₋₄—CO—NR_(1-a)R_(1-b), (n)—(CH₂)₀₋₄—SO₂—(C₁-C₆ alkyl), and (o) ═O, (p) —(CH₂)₀₋₄—N(R_(N-2))—SO₂—(q) —(CH₂)₀₋₄—N(R_(N-2))—C(O)— (8) —(CH₂)₀₋₄—CO—(C₁-C₁₂ alkyl), (9)—(CH₂)₀₋₄—CO—(C₂-C₁₂ alkenyl), (10) —(CH₂)₀₋₄—CO—(C₂-C₁₂ alkynyl), (11)—(CH₂)₀₋₄—CO—(C₃-C₈ cycloalkyl), (12) —(CH₂)₀₋₄—CO—R_(1-aryl), (13)—(CH₂)₀₋₄—CO—R_(1-heteroaryl), (14) —(CH₂)₀₋₄—CO—R_(1-heterocycle), (15)—(CH₂)₀₋₄—CO—R_(N-4) wherein R_(N-4) is selected from the groupconsisting of phenyl, morpholinyl, thiomorpholinyl, piperazinyl,piperidinyl, homomorpholinyl, homothiomorpholinyl, homothiomorpholinylS-oxide, homothiomorpholinyl S,S-dioxide, pyrrolinyl, thienyl,pyrazolyl, pyridyl N-oxide, oxazolyl, thiazolyl, imidazolyl, andpyrrolidinyl where each group is optionally substituted with one, two,three, or four groups that are independently C₁-C₆ alkyl, (16)—(CH₂)₀₋₄—CO—O—R_(N-5) where R_(N-5) is selected from the groupconsisting of: (a) C₁-C₆ alkyl, (b) —(CH₂)₀₋₂—(R_(1-aryl)), (c) C₂-C₆alkenyl, (d) C₂-C₆ alkynyl, (e) (CH₂)₀₋₂—C₃-C₈ cycloalkyl, (f)—(CH₂)₀₋₂—(R_(1-heteroaryl)), and (g) —(CH₂)₀₋₂—(R_(1-heterocycle)),(17) —(CH₂)₀₋₄—SO₂—NR_(N-2)R_(N-3), (18) —(CH₂)₀₋₄—SO—(C₁-C₈ alkyl),(19) —(CH₂)₀₋₄—SO₂—(C₁-C₁₂ alkyl), (20) —(CH₂)₀₋₄—SO₂—(C₃-C₈cycloalkyl), (21) —(CH₂)₀₋₄—N(H or R_(N-5))—CO—O—R_(N-5), (22)—(CH₂)₀₋₄—N(H or R_(N-5))—CO—N (R_(N-5))₂, (23)—(CH₂)₀₋₄—N—CS—N(R_(N-5))₂, (24) —(CH₂)₀₋₄—N(H or R_(N-5))—CO—R_(N-2),(25) —(CH₂)₀₋₄—NR_(N-2)R_(N-3), (26) —(CH₂)₀₋₄—R_(N-4), (27)—(CH₂)₀₋₄—O—CO—(C₁-C₆ alkyl), (28) —(CH₂)₀₋₄—O—P(O)—(OR₁₀₀)₂ whereinR₁₀₀ at each occurrence is independently —H or C₁-C₄ alkyl, (29)—(CH₂)₀₋₄—O—CO—N(R_(N-5))₂, (30) —(CH₂)₀₋₄—O—CS—N(R_(N-5))₂, (31)—(CH₂)₀₋₄—O—(R_(N-5)), (32) —(CH₂)₀₋₄—O—(R_(N-5))—COOH, (33)—(CH₂)₀₋₄—S—(R_(N-5)), (34) —(CH₂)₀₋₄—O—(C₁-C₆ alkyl optionallysubstituted with one, two, three, four, or five of —F), (35) C₃-C₈cycloalkyl, (36) C₂-C₆ alkenyl optionally substituted with C₁-C₃ alkyl,—F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, or—NR_(1-a)R_(1-b), (37) C₂-C₆ alkynyl optionally substituted with C₁-C₃alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, or—NR_(1-a)R_(1-b), (38) —(CH₂)₀₋₄—N(H or R_(N-5))—SO₂—R_(N-2), (39)—(CH₂)₁₋₄—(C₃-C₈ cycloalkyl), (B) —R_(N-heteroaryl) whereR_(N-heteroaryl) is selected from the group consisting of pyridinyl,indolyl, indolinyl, isoindolyl, imidazolyl, isoxazolyl, oxazolyl,thiazolyl, indolizinyl and isochromanyl, where the R_(N-heteroaryl)group is bonded by any atom of the parent R_(N-heteroaryl) groupsubstituted by hydrogen such that the new bond to the R_(N-heteroaryl)group replaces the hydrogen atom and its bond, where heteroaryl isoptionally substituted with one, two, three, or four of: (1) C₁-C₆alkyl, optionally substituted with one, two or three substituentsselected from the group consisting of C₁-C₃ alkyl, —F, —Cl, —Br, —I,—OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b), (2) —OH, (3)—NO₂, (4) —F, —Cl, —Br, —I, (5) —CO₂H, (6) —C≡N, (7)—(CH₂)₀₋₄—CO—NR_(N-2)R_(N-3), (8) —(CH₂)₀₋₄—CO—(C₁-C₁₂ alkyl), (9)—(CH₂)₀₋₄—CO—(C₂-C₁₂ alkenyl), (10) —(CH₂)₀₋₄—CO—(C₂-C₁₂ alkynyl), (11)—(CH₂)₀₋₄—CO—(C₃-C₈ cycloalkyl), (12) —(CH₂)₀₋₄—CO—R_(1-aryl), (13)—(CH₂)₀₋₄—CO—R_(1-heteroaryl), (14) —(CH₂)₀₋₄—CO—R_(1-heterocycle), (15)—(CH₂)₀₋₄—CO—R_(N-4) (16) —(CH₂)₀₋₄—CO—O—R_(N-5) (17)—(CH₂)₀₋₄—SO₂—NR_(N-2)R_(N-3), (18) —(CH₂)₀₋₄—SO—(C₁-C₈ alkyl), (19)—(CH₂)₀₋₄—SO₂—(C₁-C₁₂ alkyl), (20) —(CH₂)₀₋₄—SO₂—(C₃-C₈ cycloalkyl),(21) —(CH₂)₀₋₄—N(H or R_(N-5))—CO—O—R_(N-5), (22) —(CH₂)₀₋₄—N(H orR_(N-5))—CO—N(R_(N-5))₂, (23) —(CH₂)₀₋₄—N—CS—N(R_(N-5))₂, (24)—(CH₂)₀₋₄—N(—H or R_(N-5))—CO—R_(N-2) (25) —(CH₂)₀₋₄—NR_(N-2)R_(N-3),(26) —(CH₂)₀₋₄—R_(N-4), (27) —(CH₂)₀₋₄—O—CO—(C₁-C₆ alkyl), (28)—(CH₂)₀₋₄—O—P(O)—(OR₁₀₀)₂, (29) —(CH₂)₀₋₄—O—CO—N(R_(N-5))₂, (30)—(CH₂)₀₋₄—O—CS—N (R_(N-5))₂, (31) —(CH₂)₀₋₄—O—(R_(N-5)), (32)—(CH₂)₀₋₄—O—(R_(N-5))—COOH, (33) —(CH₂)₀₋₄—S—(R_(N-5)), (34)—(CH₂)₀₋₄—O—(C₁-C₆ alkyl optionally substituted with one, two, three,four, or five of —F), (35) C₃-C₈ cycloalkyl, (36) C₂-C₆ alkenyloptionally substituted with C₁-C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH,—C≡N, —CF₃, C₁-C₃ alkoxy, or —NR_(1-a)R_(1-b), (37) C₂-C₆ alkynyloptionally substituted with C₁-C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH,—C≡N, —CF₃, C₁-C₃ alkoxy, or —NR_(1-a)R_(1-b), (38) —(CH₂)₀₋₄—N(—H orR_(N-5))—SO₂—R_(N-2), (39) —(CH₂)₁₋₄—C₃-C₈ cycloalkyl, (C) R_(N-aryl),—W—R_(N-aryl), (D) R_(N-aryl)—W—R_(N-heteroaryl), (E)R_(N-aryl)—W—R_(1-heterocycle), , (F) R_(N-heteroaryl—W—R) _(N-aryl),(G) R_(N-heteroaryl)—W—R_(N-heteroaryl), (H)R_(N-heteroaryl)—W—R_(N-1-heterocycle), (I)R_(N-heterocycle)—W—R_(N-aryl), (J)R_(N-heterocycle)—W—R_(N heteroaryl), (K)R_(N-heterocycle)—W—R_(N-1-heterocycle), where W is (19) —(CH₂)₁₋₄—,(20) —O—, (21) —S(O)₀₋₂—, (22) —N(R_(N-5))—, (23) —CO—; or (24) a bond;(II) —CO—(C₁-C₆ alkyl)-M-(C₁-C₆ alkyl), where M is S, SO or SO₂, andwherein each alkyl is unsubstituted or substituted with one, two, orthree of substituents independently selected from the group consistingof: (A) —NH—CO—(C₁-C₆ alkyl), (B) —NH—CO—O—R_(N-8), (C)—NR_(N-2)R_(N-3); where R₁ is —(CH₂)_(n1)-phenyl, where n₁ is zero orone, and which is optionally substituted with one, two, three or four ofthe following substituents on the phenyl ring: (A) C₁-C₆ alkyloptionally substituted with one, two or three substituents selected fromthe group consisting of C₁-C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N,—CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b), (B) C₂-C₆ alkenyl with one ortwo double bonds, optionally substituted with one, two or threesubstituents selected from the group consisting of —F, —Cl, —OH, —SH,—C≡N, —CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b), (C) C₂-C₆ alkynyl withone or two triple bonds, optionally substituted with one, two or threesubstituents selected from the group consisting of —F, —Cl, —OH, —SH,—C≡N, —CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b), (D) —F, Cl, —Br or —I,(F) —C₁-C₆ alkoxy optionally substituted with one, two or three of —F,(G) —NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) are as defined below, (H)—OH, (I) —C≡N, (J) C₃-C₇ cycloalkyl, optionally substituted with one,two or three substituents selected from the group consisting of —F, —Cl,—OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b), (K) —CO-(C₁-C₄alkyl), (L) —SO₂—NR_(1-a)R_(1-b), (M) —CO—NR_(1-a)R_(1-b), (N)—SO₂—(C₁-C₄ alkyl); and where R₂ is (I) —(Z)—C₁-C₆ alkyl, where Z is abond, —C(O)—, —CO₂— or —SO₂—, wherein the alkyl group is optionallysubstituted with one, two or three substituents selected from the groupconsisting of C₁-C₃ alkyl, C₁-C₇ alkyl (optionally substituted withC₁-C₃ alkyl and C₁-C₃ alkoxy), —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃,C₁-C₃ alkoxy, —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) areindependently —H or C₁-C₆ alkyl, and —OC≡O NR_(1-a)R_(1-b), (II)—(Z)—CH₂—S(O)₀₋₂—(C₁-C₆ alkyl), (III) —(Z)—CH₂-CH₂—S(O)₀₋₂—(C₁-C₆alkyl), (IV) —(Z)—C₂-C₆ alkenyl with one or two double bonds, optionallysubstituted with one, two or three substituents selected from the groupconsisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and—NR_(1-a)R_(1-b), (V) —(Z)—C₂-C₆ alkynyl with one or two triple bonds,optionally substituted with one, two or three substituents selected fromthe group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and—NR_(1-a)R_(1-b), (VI) —(Z)—(CH₂)_(n1)—(R_(1-aryl)), where Z is a bond,CO, CO₂ or SO₂, where n₁ is zero or one and where R_(1-aryl) is phenyl,1-naphthyl, 2-naphthyl and indanyl, indenyl, dihydronaphthalyl, ortetralinyl optionally substituted with one, two, three or four of thefollowing substituents on the aryl ring: (A) C₁-C₆ alkyl optionallysubstituted with one, two or three substituents selected from the groupconsisting of C₁-C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁-C₃alkoxy, and —NR_(1-a)R_(1-b), (B) C₂-C₆ alkenyl with one or two doublebonds, optionally substituted with one, two or three substituentsselected from the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃,C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b), (C) C₂-C₆ alkynyl with one or twotriple bonds, optionally substituted with one, two or three substituentsselected from the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃,C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b), (D) —F, Cl, —Br or —I, (F) —C₁-C₆alkoxy optionally substituted with one, two or three of —F, (G)—NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) are as defined below, (H)—OH, (I) —C≡N, (J) C₃-C₇ cycloalkyl, optionally substituted with one,two or three substituents selected from the group consisting of —F, —Cl,—OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b), (K) —CO—(C₁-C₄alkyl), (L) —SO₂-NR_(1-a)R_(1-b), (M) —CO—NR_(1-a)R_(1-b), (N)—SO₂—(C₁-C₄ alkyl), (VII) —(Z)—(CH₂)_(n1)—(R_(1-heteroaryl)) where n₁ isas defined above and where R_(1-heteroaryl) is selected from the groupconsisting of: pyridinyl, pyrimidinyl, quinolinyl, benzothienyl,indolyl, indolinyl, pryidazinyl, pyrazinyl, isoindolyl, isoquinolyl,quinazolinyl, quinoxalinyl, phthalazinyl, imidazolyl, isoxazolyl,pyrazolyl, oxazolyl, thiazolyl, indolizinyl, indazolyl, benzothiazolyl,benzimidazolyl, benzofuranyl, furanyl, thienyl, pyrrolyl, oxadiazolyl,thiadiazolyl, triazolyl, tetrazolyl, oxazolopyridinyl, imidazopyridinyl,isothiazolyl, naphthyridinyl, cinnolinyl, carbazolyl, beta-carbolinyl,isochromanyl, chromanyl, tetrahydroisoquinolinyl, isoindolinyl,isobenzotetrahydrofuranyl, isobenzotetrahydrothienyl, isobenzothienyl,benzoxazolyl, pyridopyridinyl, benzotetrahydrofuranyl,benzotetrahydrothienyl, purinyl, benzodioxolyl, triazinyl, phenoxazinyl,phenothiazinyl, pteridinyl, benzothiazolyl, imidazopyridinyl,imidazothiazolyl, dihydrobenzisoxazinyl, benzisoxazinyl, benzoxazinyl,dihydrobenzisothiazinyl, benzopyranyl, benzothiopyranyl, coumarinyl,isocoumarinyl, chromonyl, chromanonyl, pyridinyl-N-oxide,tetrahydroquinolinyl, dihydroquinolinyl, dihydroquinolinonyl,dihydroisoquinolinonyl, dihydrocoumarinyl, dihydroisocoumarinyl,isoindolinonyl, benzodioxanyl, benzoxazolinonyl, pyrrolyl N-oxide,pyrimidinyl N-oxide, pyridazinyl N-oxide, pyrazinyl N-oxide, quinolinylN-oxide, indolyl N-oxide, indolinyl N-oxide, isoquinolyl N-oxide,quinazolinyl N-oxide, quinoxalinyl N-oxide, phthalazinyl N-oxide,imidazolyl N-oxide, isoxazolyl N-oxide, oxazolyl N-oxide, thiazolylN-oxide, indolizinyl N-oxide, indazolyl N-oxide, benzothiazolyl N-oxide,benzimidazolyl N-oxide, pyrrolyl N-oxide, oxadiazolyl N-oxide,thiadiazolyl N-oxide, triazolyl N-oxide, tetrazolyl N-oxide,benzothiopyranyl S-oxide, benzothiopyranyl S,S-dioxide, where theR_(1-heteroaryl) group is bonded to —(CH₂)_(n1)— by any ring atom of theparent R_(N-heteroaryl) group substituted by hydrogen such that the newbond to the R_(1-heteroaryl) group replaces the hydrogen atom and itsbond, where heteroaryl is optionally substituted with one, two, three orfour of: (1) C₁-C₆ alkyl optionally substituted with one, two or threesubstituents selected from the group consisting of C₁-C₃ alkyl, —F, —Cl,—Br, —I, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b), (2)C₂-C₆ alkenyl with one or two double bonds, optionally substituted withone, two or three substituents selected from the group consisting of —F,—Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b), (3) C₂-C₆alkynyl with one or two triple bonds, optionally substituted with one,two or three substituents selected from the group consisting of —F, —Cl,—OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b), (4) —F, Cl,—Br or —I, (6) —C₁-C₆ alkoxy optionally substituted with one, two, orthree of —F, (7) —NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) are asdefined below, (8) —OH, (9) —C≡N, (10) C₃-C₇ cycloalkyl, optionallysubstituted with one, two or three substituents selected from the groupconsisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and—NR_(1-a)R_(1-b), (11) —CO-(C₁-C₄ alkyl), (12) —SO₂—NR_(1-a)R_(1-b),(13) —CO—NR_(1-a)R_(1-b), or (14) —SO₂-(C₁-C₄ alkyl), with the provisothat when n₁ is zero R_(1-heteroaryl) is not bonded to the carbon chainby nitrogen, or (VIII) —(Z)—(CH₂)_(n1)—(R_(1-heterocycle)) where n₁ isas defined above and R_(1-heterocycle) is selected from the groupconsisting of: morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide,thiomorpholinyl S,S-dioxide, piperazinyl, homopiperazinyl, pyrrolidinyl,pyrrolinyl, tetrahydropyranyl, piperidinyl, tetrahydrofuranyl,tetrahydrothienyl, homopiperidinyl, homomorpholinyl, homomorpholinylS-oxide, homothiomorpholinyl S,S-dioxide, oxazolidinonyl,dihydropyrazolyl, dihydropyrrolyl dihydropyrazinyl dihydropyridinyldihydropyrimidinyl, dihydrofuryl, dihydropyranyl, tetrahydrothienylS-oxide, tetrahydrothienyl S,S-dioxide, homothiomorpholinyl S-oxide,where the R_(1-heterocycle) group is bonded by any atom of the parentR_(1-heterocycle) group substituted by hydrogen such that the new bondto the R_(1-heterocycle) group replaces the hydrogen atom and its bond,where heterocycle is optionally substituted with one, two, three orfour: (1) C₁-C₆ alkyl optionally substituted with one, two or threesubstituents selected from the group consisting of C₁-C₃ alkyl, —F, —Cl,—Br, —I, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b), (2)C₂-C₆ alkenyl with one or two double bonds, optionally substituted withone, two or three substituents selected from the group consisting of —F,—Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b), (3) C₂-C₆alkynyl with one or two triple bonds, optionally substituted with one,two or three substituents selected from the group consisting of —F, —Cl,—OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b), (4) —F, Cl,—Br, or —I, (5) C₁-C₆ alkoxy, (6) —C₁-C₆ alkoxy optionally substitutedwith one, two, or three —F, (7) —NR_(N-2)R_(N-3) where R_(N-2) andR_(N-3) are as defined below, (8) —OH, (9) —C≡N, (10) C₃-C₇ cycloalkyl,optionally substituted with one, two or three substituents selected fromthe group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and—NR_(1-a)R_(1-b), (11) —CO-(C₁-C₄ alkyl) (12) —SO₂—NR_(1-a)R_(1-b), (13)—CO—NR_(1-a)R_(1-b), (14) —SO₂-(C₁-C₄ alkyl) (15) ═O, with the provisothat when n₁ is zero R_(1-heterocycle) is not bonded to the carbon chainby nitrogen; and where R₂₀ is H or C₁₋₆ alkyl or alkenyl.
 2. A compoundaccording to claim 1, wherein Rc is —(CR_(C-x)R_(C-y))₀₋₄—R_(C-aryl)where R_(C-x) and R_(C-y) are independently selected from the groupconsisting of —H, C₁-C₄ alkyl optionally substituted with 1 or 2 —OH,C₁-C₄ alkoxy optionally substituted with 1, 2, or 3 halogen,—(CH₂)₀₋₄—C₃-C₈ cycloalkyl, C₂-C₆ alkenyl containing one or two doublebonds, C₂-C₆ alkynyl containing one or two triple bonds, and phenyl, orR_(C-x) and R_(C-y) are taken together with the carbon to which they areattached to form a carbocycle of three, four, five, six or seven carbonatoms, where one carbon atom is optionally replaced by a group selectedfrom —O—, —S—, —SO₂—, —NR_(N-2)— and R_(C-aryl), wherein R_(C-aryl) isphenyl, which is optionally substituted with 1, 2, or 3 groups that areindependently: (1) C₁-C₆ alkyl, optionally substituted with one, two orthree substituents selected from the group consisting of C₁-C₃ alkyl,halogen, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b), (2)—OH, (3) —NO₂, (4) halogen, (5) —CO₂H, (6) —C≡N.
 3. A compound accordingto claim 1, wherein Rc is —(CR_(C-x)R_(C-y))₀₋₄—R_(C-aryl) where R_(C-x)and R_(C-y) are independently selected from the group consisting of —H,C₁-C₄ alkyl optionally substituted with 1 or 2 —OH, C₁-C₄ alkoxyoptionally substituted with 1, 2, or 3 halogen, —(CH₂)₀₋₄—C₃-C₈cycloalkyl, C₂-C₆ alkenyl containing one or two double bonds, C₂-C₆alkynyl containing one or two triple bonds, and phenyl, or R_(C-x) andR_(C-y) are taken together with the carbon to which they are attached toform a carbocycle of three, four, five, six or seven carbon atoms, whereone carbon atom is optionally replaced by a group selected from —O—,—S—, —SO₂—, —NR_(N-2)— and R_(C-aryl), wherein—(CR_(C-x)R_(C-y))₀₋₄—R_(C-heteroaryl) is selected from the groupconsisting of pyridinyl, indolyl, indolinyl, isoindolyl, imidazolyl,isoxazolyl, oxazolyl, thiazolyl, indolizinyl and isochromanyl.
 4. Acompound according to claim 1, of the formula:


5. A compound according to claim 1, of the formula:


6. A compound according to claim 1, of the formula:


7. A compound according to claim 1, of the formula:


8. A compound according to claim 1, of the formula:


9. A compound of the formula III:

or a pharmaceutically acceptable salt thereof wherein R₁ representsphenyl (C₁-C₆)alkyl where the phenyl is optionally substituted with upto three groups independently selected from halogen, hydroxy, C₁-C₂alkyl, C₁-C₂ alkoxy, amino, nitro, trifluoromethyl, cyano,mono(C₁-C₂)alkylamino and di (C₁-C₂) alkylamino; R_(a) and R_(b)independently represent hydrogen, hydroxy, C₁-C₆ alkyl, C₁-C₆ alkoxy,C₃-C₇ cycloalkyl, C₃-C₇ cycloalkyl(C₁-C₆)alkyl, C₃-C₇cycloalkyl(C₁-C₆)alkoxy, halogen, cyano, amino, mono(C₁-C₆)alkylamino,di(C₁-C₆)alkylamino, mono- or di(C₁-C₆)alkylaminosulfonyl, C₁-C₆ alkylsulfonylamino, C₂-C₆ alkenyl, C₂-C₆ alkynyl, trifluoromethyl,mono(C₁-C₆)alkylaminocarbonyl, or di (C₁-C₆) alkylaminocarbonyl andprovided that not both R_(a) and R_(b) are hydrogen simultaneously;R_(c) represents hydrogen, or C₁-C₆ alkyl, C₂-C₆ alkenyl, or C₂-C₆alkynyl each of which is optionally substituted with halogen, hydroxy,amino, cyano, or trifluoromethyl; R_(d) represents phenyl optionallysubstituted with hydroxy, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₃-C₇ cycloalkyl,C₃-C₇ cycloalkyl(C₁-C₆)alkyl, C₃-C₇ cycloalkyl(C₁-C₆)alkoxy, halogen,cyano, amino, mono(C₁-C₆)alkylamino, di(C₁-C₆)alkylamino, mono- ordi(C₁-C₆)alkylaminosulfonyl, C₁-C₆ alkyl sulfonylamino, C₂-C₆ alkenyl,C₂-C₆ alkynyl; or C₁-C₆ alkyl optionally substituted with hydroxy, C₁-C₆alkyl, C₁-C₆ alkoxy, halogen, cyano, amino, mono(C₁-C₆)alkylamino,di(C₁-C₆)alkylamino, C₂-C₆ alkenyl, C₂-C₆ alkynyl, or trifluoromethyl;and R₂₀ represents hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,or trifluoromethyl.
 10. A compound according to claim 9, wherein R₁ isbenzyl where the phenyl is optionally substituted.
 11. A compoundaccording to claim 10, wherein the phenyl is substituted with one or twogroups independently selected from halogen, hydroxy, C₁-C₃ alkyl, amino,and trifluoromethyl.
 12. A compound according to claim 11, whereinphenyl is substituted with two groups independently selected fromhalogen, hydroxy, and trifluoromethyl.
 13. A compound according to claim12, wherein phenyl is disubstituted with halogen.
 14. A compoundaccording to claim 13, wherein R₁ is 3,5-difluorobenzyl.
 15. A compoundaccording to claim 12, wherein R_(a) and R_(b) are different and R_(b)represents mono- or di(C₁-C₆)alkylaminocarbonyl.
 16. A compoundaccording to claim 12, wherein R_(d) is phenyl optionally substitutedwith C₁-C₃ alkyl, C₁-C₃ alkoxy, amino, hydroxy, or halogen.
 17. Acompound according to claim 12, wherein R_(c) is hydrogen or C₁-C₄alkyl.
 18. A compound according to claim 17, wherein R_(c) is C₁-C₃alkyl.
 19. A compound according to claim 12, wherein R_(d) is C₁-C₆lower alkyl and R₂₀ is hydrogen.
 20. A compound according to claim 12,which has the formula IV:


21. A compound according to claim 20, wherein R₁ is benzyl where thephenyl is disubstituted with chloro or fluoro; R_(c) is C₁-C₃ alkyl;R_(d) is C₁-C₆ lower alkyl; R₂₀ is hydrogen or C₁-C₆ alkyl; and R_(b) isdi(C₁-C₆)alkylaminocarbonyl attached to the 3-position of the phenylgroup.
 22. A compound of the formula V:

or a pharmaceutically acceptable salt thereof wherein R₁ representsphenyl (C₁-C₆)alkyl where the phenyl is optionally substituted with upto three groups independently selected from halogen, hydroxy, C₁-C₂alkyl, C₁-C₂ alkoxy, amino, nitro, trifluoromethyl, cyano,mono(C₁-C₂)alkylamino and di(C₁-C₂) alkylamino; R_(a) and R_(b)independently represent hydrogen, hydroxy, C₁-C₆ alkyl, C₁-C₆ alkoxy,C₃-C₇ cycloalkyl, C₃-C₇ cycloalkyl(C₁-C₆)alkyl, C₃-C₇ cycloalkyl(C₁-C₆)alkoxy, halogen, cyano, amino, mono(C₁-C₆)alkylamino,di(C₁-C₆)alkylamino, mono- or di(C₁-C₆)alkylaminosulfonyl, C₁-C₆ alkylsulfonylamino, C₂-C₆ alkenyl, C₂-C₆ alkynyl, trifluoromethyl,mono(C₁-C₆)alkylaminocarbonyl, C₆)alkylaminocarbonyl, or di(C₁-C₆)alkylaminocarbonyl and provided that not both R_(a) and R_(b) arehydrogen simultaneously; R_(c) represents hydrogen, or C₁-C₆ alkyl,C₂-C₆ alkenyl, or C₂-C₆ alkynyl each of which is optionally substitutedwith halogen, hydroxy, amino, cyano, or trifluoromethyl; R_(d)represents phenyl optionally substituted with hydroxy, C₁-C₆ alkyl,C₁-C₆ alkoxy, C₃-C₇ cycloalkyl, C₃-C₇ cycloalkyl(C₁-C₆)alkyl, C₃-C₇cycloalkyl(C₁-C₆)alkoxy, halogen, cyano, amino, mono(C₁-C₆)alkylamino,di(C₁-C₆)alkylamino, mono- or di (C₁-C₆)alkylaminosulfonyl, C₁-C₆ alkylsulfonylamino, C₂-C₆ alkenyl, C₂-C₆ alkynyl; or C₁-C₆ alkyl optionallysubstituted with hydroxy, C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, cyano,amino, mono(C₁- C₆)alkylamino, di(C₁-C₆)alkylamino, C₂-C₆ alkenyl, C₂-C₆alkynyl, or trifluoromethyl; and R₂₀ represents hydrogen, C₁-C₆ alkyl,C₂-C₆ alkenyl, C₂-C₆ alkynyl, or trifluoromethyl.
 23. A compoundaccording to claim 22, wherein R₁ is benzyl where the phenyl isoptionally substituted.
 24. A compound according to claim 23, whereinthe phenyl is substituted with one or two groups independently selectedfrom halogen, hydroxy, C₁-C₃ alkyl, amino, and trifluoromethyl.
 25. Acompound according to claim 24, wherein phenyl is substituted with twogroups independently selected from halogen, hydroxy, andtrifluoromethyl.
 26. A compound according to claim 25, wherein phenyl isdisubstituted with halogen.
 27. A compound according to claim 26,wherein R₁ is 3,5-difluorobenzyl.
 28. A compound according to claim 25,wherein R_(a) and R_(b) are different and R_(b) representsC₁-C₆)alkylsulfonylamino.
 29. A compound according to claim 25, whereinR_(d) is phenyl optionally substituted with C₁-C₃ alkyl, C₁-C₃ alkoxy,amino, hydroxy, or halogen.
 30. A compound according to claim 25,wherein R_(c) is hydrogen or C₁-C₄ alkyl.
 31. A compound according toclaim 30, wherein R_(c) is C₁-C₃ alkyl.
 32. A compound according toclaim 25, wherein R_(d) is C₁-C₆ lower alkyl and R₂₀ is hydrogen.
 33. Acompound according to claim 25, which has the formula VI:


34. A compound according to claim 33, wherein R₁ is benzyl where thephenyl is disubstituted with chloro or fluoro; R_(c) is C₁-C₃ alkyl;R_(d) is C₁-C₆ lower alkyl; R₂₀ is hydrogen or C₁-C₆ alkyl; and R_(b) isalkylsulfonylamino attached to the 2-position of the thiazolyl group.35. A compound according to claim 1, selected from the group consistingof:


36. A method of treating a patient who has, or in preventing a patientfrom getting, a disease or condition selected from the group consistingof Alzheimer's disease, for helping prevent or delay the onset ofAlzheimer's disease, for treating patients with mild cognitiveimpairment (MCI) and preventing or delaying the onset of Alzheimer'sdisease in those who would progress from MCI to AD, for treating Down'ssyndrome, for treating humans who have Hereditary Cerebral Hemorrhagewith Amyloidosis of the Dutch-Type, for treating cerebral amyloidangiopathy and preventing its potential consequences, i.e. single andrecurrent lobar hemorrhages, for treating other degenerative dementias,including dementias of mixed vascular and degenerative origin, dementiaassociated with Parkinson's disease, dementia associated withprogressive supranuclear palsy, dementia associated with cortical basaldegeneration, diffuse Lewy body type of Alzheimer's disease and who isin need of such treatment which comprises administration of atherapeutically effective amount of a compound selected from the groupconsisting of an aza hydroxylated ethyl amine of the formula II:

or a pharmaceutically acceptable salt thereof, where Rc is (I) —C₁-C₁₀alkyl optionally substituted with one, two or three groups independentlyselected from the group consisting of C₁-C₃ alkyl, halogen, —OH, —SH,—C≡N, —CF₃, C₁-C₆ alkoxy, —O—phenyl, —NR_(1-a)R_(1-b), —OC═ONR_(1-a)R_(1-b), —S(═O)₀₋₂ R_(1-a), —NR_(1-a)C═O NR_(1-a)R_(1-b), —C═ONR_(1-a)R_(1-b), and —S(═O)₂ NR_(1-a)R_(1-b) wherein R_(1-a) and R_(1-b)at each occurrence are independently H or C₁-C₆ alkyl, (II)—(CH₂)₀₋₃—(C₃-C₈) cycloalkyl where cycloalkyl can be optionallysubstituted with one, two or three substituents independently selectedfrom the group consisting of C₁-C₃ alkyl, halogen, —OH, —SH, —C≡N, —CF₃,C₁-C₆ alkoxy, —O-phenyl, —CO₂H, —CO₂-(C₁-C₄ alkyl) , and—NR_(1-a)R_(1-b) (III) —(CR_(C-x)R_(C-y))₀₋₄—R_(C-aryl) where R_(C-x)and R_(C-y) are independently selected from the group consisting of —H,C₁-C₄ alkyl optionally substituted with 1 or 2 —OH, C₁-C₄ alkoxyoptionally substituted with 1, 2, or 3 halogen, —(CH₂)₀₋₄—C₃-C₈cycloalkyl, C₂-C₆ alkenyl containing one or two double bonds, C₂-C₆alkynyl containing one or two triple bonds, and phenyl, or R_(C-x) andR_(C-y) are taken together with the carbon to which they are attached toform a carbocycle of three, four, five, six or seven carbon atoms, whereone carbon atom is optionally replaced by a group selected from —O—,—S—, —SO₂—, —NR_(N-2)— and R_(C-aryl), wherein R_(C-aryl) is phenyl,which is optionally substituted with 1, 2, or 3 groups that areindependently: (1) C₁-C₆ alkyl, optionally substituted with one, two orthree substituents selected from the group consisting of C₁-C₃ alkyl,halogen, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b), (2)—OH, (3) —NO₂, (4) halogen, (5) —CO₂H, (6) —C≡N, (7)—(CH₂)₀₋₄—CO—NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) are independentlyselected from the group consisting of: (a) —H, (b) —C₁-C₆ alkyloptionally substituted with one substituent selected from the groupconsisting of: (i) —OH, and (ii) —NH₂, (c) —C₁-C₆ alkyl optionallysubstituted with 1, 2, or 3 groups that are independently —F, —Cl, —Br,—I, or OH, (d) —C₃-C₇ cycloalkyl, (e) —(C₁-C₂ alkyl)-(C₃-C₇ cycloalkyl),(f) —(C₁-C₆ alkyl)-O-(C₁-C₃ alkyl) (g) —C₂-C₆ alkenyl (h) —C₂-C₆ alkynyl(i) —C₁-C₆ alkyl chain with one double bond and one triple bond, (j)—R_(1-aryl) wherein R_(1-aryl) at each occurrence is independentlyphenyl, naphthyl, indanyl, indenyl, dihydronaphthyl, or tetralinyl eachof which is optionally substituted with 1, 2, 3, or 4 groups that areindependently: (i) C₁-C₆ alkyl optionally substituted with one, two orthree substituents independently selected from the group consisting ofC₁-C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH, —NR_(1-a)R_(1-b), —C≡N, —CF₃,and C₁-C₃ alkoxy, (ii) C₂-C₆ alkenyl with one or two double bonds,optionally substituted with one, two or three substituents independentlyselected from the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃,C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b), (iii) C₂-C₆ alkynyl optionallysubstituted with 1, 2, or 3 groups that are independently selected fromthe group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and—NR_(1-a)R_(1-b), (iv) —F, Cl, —Br and —I, (v) —C₁-C₆ alkoxy optionallysubstituted with 1, 2, or 3 —F, (vi) —NR_(N-2)R_(N-3), (vii) —OH, (viii)—C≡N, (ix) C₃-C₇ cycloalkyl, optionally substituted with 1, 2, or 3groups that are selected from the group consisting of —F, —Cl, —OH, —SH,—C≡N, —CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b), (x) —CO-(C₁-C₄ alkyl),(xi) —SO₂—NR_(1-a)R_(1-b), (xii) —CO—NR_(1-a)R_(1-b), or (xiii)—SO₂-(C₁-C₄ alkyl) (k) —R_(1-heteroaryl) wherein R_(1-heteroaryl) ateach occurrence is independently selected from the group consisting ofpyridinyl, pyrimidinyl, quinolinyl, benzothienyl, indolyl, indolinyl,pryidazinyl, pyrazinyl, isoindolyl, isoquinolyl, quinazolinyl,quinoxalinyl, phthalazinyl, imidazolyl, isoxazolyl, pyrazolyl, oxazolyl,thiazolyl, indolizinyl, indazolyl, benzothiazolyl, benzimidazolyl,benzofuranyl, furanyl, thienyl, pyrrolyl, oxadiazolyl, thiadiazolyl,triazolyl, tetrazolyl, oxazolopyridinyl, imidazopyridinyl, isothiazolyl,naphthyridinyl, cinnolinyl, carbazolyl, beta-carbolinyl, isochromanyl,chromanyl, tetrahydroisoquinolinyl, isoindolinyl,isobenzotetrahydrofuranyl, isobenzotetrahydrothienyl, isobenzothienyl,benzoxazolyl, pyridopyridinyl, benzotetrahydrofuranyl,benzotetrahydrothienyl, purinyl, benzodioxolyl, triazinyl, phenoxazinyl,phenothiazinyl, pteridinyl, benzothiazolyl, imidazopyridinyl,imidazothiazolyl, dihydrobenzisoxazinyl, benzisoxazinyl, benzoxazinyl,dihydrobenzisothiazinyl, benzopyranyl, benzothiopyranyl, coumarinyl,isocoumarinyl, chromonyl, chromanonyl, pyridinyl-N-oxide,tetrahydroquinolinyl, dihydroquinolinyl, dihydroquinolinonyl,dihydroisoquinolinonyl, dihydrocoumarinyl, dihydroisocoumarinyl,isoindolinonyl, benzodioxanyl, benzoxazolinonyl, pyrrolyl N-oxide,pyrimidinyl N-oxide, pyridazinyl N-oxide, pyrazinyl N-oxide, quinolinylN-oxide, indolyl N-oxide, indolinyl N-oxide, isoquinolyl N-oxide,quinazolinyl N-oxide, quinoxalinyl N-oxide, phthalazinyl N-oxide,imidazolyl N-oxide, isoxazolyl N-oxide, oxazolyl N-oxide, thiazolylN-oxide, indolizinyl N-oxide, indazolyl N-oxide, benzothiazolyl N-oxide,benzimidazolyl N-oxide, pyrrolyl N-oxide, oxadiazolyl N-oxide,thiadiazolyl N-oxide, triazolyl N-oxide, tetrazolyl N-oxide,benzothiopyranyl S-oxide, and benzothiopyranyl S,S-dioxide, where theR_(1-heteroaryl) group is optionally substituted with 1, 2, 3, or 4groups that are independently: (i) C₁-C₆ alkyl optionally substitutedwith 1, 2, or 3 groups independently selected from the group consistingof C₁-C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH, —NR_(1-a)R_(1-b), —C≡N,—CF₃, and C₁-C₃ alkoxy, (ii) C₂-C₆ alkenyl optionally substituted with1, 2, or 3 groups that are independently —F, —Cl, —OH, —SH, —C≡N, —CF₃,C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b), (iii) C₂-C₆ alkynyl optionallysubstituted with 1, 2, or 3 groups that are independently selected fromthe group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and—NR_(1-a)R_(1-b), (iv) —F, —Cl, —Br and —I, (v) —C₁-C₆ alkoxy optionallysubstituted with one, two, or three —F, (vi) —(CH₂)₀₋₄—NR_(N-2)R_(N-3),(vii) —OH, (viii) —C≡N, (ix) (CH₂)₀₋₄—C₃-C₇ cycloalkyl, optionallysubstituted with 1, 2, or 3 groups that are independently selected fromthe group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and—NR_(1-a)R_(1-b), (x) (CH₂)₀₋₄—CO-(C₁-C₆ alkyl), (xi)(CH₂)₀₋₄—SO₂—NR_(N-2)R_(N-3), (xii) (CH₂)₀₋₄—CO—NR_(N-2)R_(N-3), (xiii)(CH₂)₀₋₄—SO₂-(C₁-C₆ alkyl), (xiv) (CH₂)₀₋₄—N (R_(N-2))—SO₂—, and (xv)(CH₂)₀₋₄—N(R_(N-2))—C(O)—, (8) —(CH₂)₀₋₄—CO-(C₁-C₁₂ alkyl), (9)—(CH₂)₀₋₄—CO-(C₂-C₁₂ alkenyl), (10) —(CH₂)₀₋₄—CO-(C₂-C₁₂ alkynyl), (11)—(CH₂)₀₋₄—CO—(CH₂)₀₋₄ (C₃-C₇ cycloalkyl), (12) —(CH₂)₀₋₄—CO—R_(1-aryl),(13) —(CH₂)₀₋₄—CO—R_(1-heteroaryl), (14) —(CH₂)₀₋₄—CO—R_(1-heterocycle)wherein R_(1-heterocycle) at each occurrence is independently selectedfrom the group consisting of morpholinyl, thiomorpholinyl,thiomorpholinyl S-oxide, thiomorpholinyl S,S-dioxide, piperazinyl,homopiperazinyl, pyrrolidinyl, pyrrolinyl, tetrahydropyranyl,piperidinyl, tetrahydrofuranyl, tetrahydrothienyl, homopiperidinyl,homomorpholinyl, homothiomorpholinyl, homothiomorpholinyl S,S-dioxide,oxazolidinonyl, dihydropyrazolyl, dihydropyrrolyl, dihydropyrazinyl,dihydropyridinyl, dihydropyrimidinyl, dihydrofuryl, dihydropyranyl,tetrahydrothienyl S-oxide, tetrahydrothienyl S,S-dioxide, andhomothiomorpholinyl S-oxide, where the R_(1-heterocycle) group is bondedby any atom of the parent R_(1-heterocycle) group substituted byhydrogen such that the new bond to the R_(1-heterocycle) group replacesthe hydrogen atom and its bond, where heterocycle is optionallysubstituted with 1, 2, 3, or 4 groups that are independently: (a) C₁-C₆alkyl optionally substituted with one, two or three substituentsindependently selected from the group consisting of C₁-C₃ alkyl,halogen, —OH, —SH, —NR_(1-a)R_(1-b) —C≡N, —CF₃, and C₁-C₃ alkoxy, (b)C₂-C₆ alkenyl with one or two double bonds, optionally substituted withone, two or three substituents independently selected from the groupconsisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and—NR_(1-a)R_(1-b) (c) C₂-C₆ alkynyl with one or two triple bonds,optionally substituted with one, two or three substituents independentlyselected from the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃,C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b) (d) halogen, (e) C₁-C₆ alkoxy, (f)—C₁-C₆ alkoxy optionally substituted with one, two, or three —F, (g)—NR_(N-2)R_(N-3), (h) —OH, (i) —C≡N, (j) (CH₂)₀₋₄-(C₃-C₇ cycloalkyl),optionally substituted with 1, 2, or 3 groups independently selectedfrom the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃alkoxy, and —NR_(1-a)R_(1-b), (k) —(CH₂)₀₋₄—CO-(C₁-C₄ alkyl), (l)—(CH₂)₀₋₄—SO₂—NR_(1-a)R_(1-b), (m) —(CH₂)₀₋₄—CO—NR_(1-a)R_(1-b), (n)—(CH₂)₀₋₄—SO₂-(C₁-C₆ alkyl), and (o) ═O, (p) —(CH₂)₀₋₄—N(R_(N-2))—SO₂—(q) —(CH₂)₀₋₄—N(R_(N-2))—C(O)— (15) —(CH₂)₀₋₄—CO—R_(N-4) wherein R_(N-4)at each occurrence is independently selected from the group consistingof morpholinyl, thiomorpholinyl, pyrrolidinonyl, pyrrolyl, pyrazolyl,thienyl, pyridyl N-oxide, piperazinyl, piperidinyl, homomorpholinyl,homothiomorpholinyl, homothiomorpholinyl S-oxide, homothiomorpholinylS,S-dioxide, pyrrolinyl and pyrrolidinyl where each group is optionallysubstituted with 1, 2, 3, or 4 groups that are independently C₁-C₆alkyl, (16) —(CH₂)₀₋₄—CO₂—R_(N-5) where R_(N-5) at each occurrence isindependently selected from the group consisting of: (a) C₁-C₆ alkyl,(b) —(CH₂)₀₋₂—(R_(1-aryl)), (c) C₂-C₆ alkenyl, (d) C₂-C₆ alkynyl, (e)C₃-C₇ cycloalkyl, and (f) —(CH₂)₀₋₄—(R_(1-heteroaryl)), (17)—(CH₂)₀₋₄—SO₂—NR_(N-2)R_(N-3) (18) —(CH₂)₀₋₄—SO-(C₁-C₈ alkyl), (19)—(CH₂)₀₋₄—SO₂-(C₁-C₁₂ alkyl), (20) —(CH₂)₀₋₄—SO₂-(C₃-C₇ cycloalkyl),(21) —(CH₂)₀₋₄—N(H or R_(N-5))—CO₂—R_(N-5), (22) —(CH₂)₀₋₄—N(H orR_(N-5))—CO—N(R_(N-5))₂, (23) —(CH₂)₀₋₄—N—CS—N(R_(N-5))₂, (24)—(CH₂)₀₋₄—N(—H or R_(N-5))—CO—R_(N-2), (25) —(CH₂)₀₋₄—NR_(N-2)R_(N-3),(26) —(CH₂)₀₋₄—R_(N-4), (27) —(CH₂)₀₋₄—O—CO-(C₁-C₆ alkyl), (28)—(CH₂)₀₋₄—O—-P(O)—(OR₁₀₀)₂ where R₁₀₀ is independently H or C₁-C₄ alkyl,(29) —(CH₂)₀₋₄—O—CO—N(R_(N-5))₂, (30) —(CH₂)₀₋₄—O—CS—N (R_(N-5))₂, (31)—(CH₂)₀₋₄—O—(R_(N-5)), (32) —(CH₂)₀₋₄—O—(R_(N-5))—COOH, (33)—(CH₂)₀₋₄—S—(R_(N-5)), (34) —(CH₂)₀₋₄—O-(C₁-C₆ alkyl) wherein the alkylgroup is optionally substituted with one, two, three, four, or fivesubstituents independently selected from the group consisting of F, Cl,Br, and I, (35) —(CH₂)₀₋₄-(C₃-C₈ cycloalkyl), (36) C₂-C₆ alkenyloptionally substituted with C₁-C₃ alkyl, halogen, —OH, —SH, —C≡N, —CF₃,C₁-C₃ alkoxy, or —NR_(1-a)R_(1-b), (37) C₂-C₆ alkynyl optionallysubstituted with C₁-C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃,C₁-C₃ alkoxy, or —NR_(1-a)R_(1-b), and (38) —(CH₂)₀₋₄—N(—H orR_(N-5))—SO₂—R_(N-2); (IV) —(CR_(C-x)R_(C-y))₀₋₄—R_(C-heteroaryl)wherein R_(C-heteroaryl) at each occurrence is independently selectedfrom the group consisting of pyridinyl, pyrimidinyl, quinolinyl,benzothienyl, indolyl, indolinyl, pryidazinyl, pyrazinyl, isoindolyl,isoquinolyl, quinazolinyl, quinoxalinyl, phthalazinyl, imidazolyl,isoxazolyl, pyrazolyl, oxazolyl, thiazolyl, indolizinyl, indazolyl,benzoisothiazolyl, benzimidazolyl, benzofuranyl, furanyl, thienyl,pyrrolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl,oxazolopyridinyl, isothiazolyl, naphthyridinyl, cinnolinyl, carbazolyl,beta-carbolinyl, isochromanyl, chromanyl, tetrahydroisoquinolinyl,isoindolinyl, isobenzotetrahydrofuranyl, isobenzotetrahydrothienyl,isobenzothienyl, benzoxazolyl, pyridopyridinyl, benzotetrahydrofuranyl,benzotetrahydrothienyl, purinyl, benzodioxolyl, triazinyl, henoxazinyl,phenothiazinyl, pteridinyl, benzothiazolyl, imidazopyridinyl,imidazothiazolyl, dihydrobenzisoxazinyl, benzisoxazinyl, benzoxazinyl,dihydrobenzisothiazinyl, benzopyranyl, benzothiopyranyl, coumarinyl,isocoumarinyl, chromonyl, chromanonyl, tetrahydroquinolinyl,dihydroquinolinyl, dihydroquinolinonyl,dihydroisoquinolinonyl,dihydrocoumarinyl, dihydroisocoumarinyl,isoindolinonyl, benzodioxanyl, benzoxazolinonyl, imidazopyrazolyl,quinazolinonyl, pyrazopyridyl, benzooxadiazolyl, dihydropyrimidinonyl,dihydrobenzofuranonyl, where the R_(C-heteroaryl) group is bonded by anyatom of the parent R_(C-heteroaryl) group substituted by hydrogen suchthat the new bond to the R_(C-heteroaryl) group replaces the hydrogenatom and its bond, where heteroaryl is optionally substituted 1, 2, 3,or 4 groups that are independently: (1) C₁-C₆ alkyl, optionallysubstituted with 1, 2, or 3 groups independently selected from the groupconsisting of C₁-C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁-C₃alkoxy, and —NR_(1-a)R_(1-b), (2) —OH, (3) —NO₂, (4) —F, —Cl, —Br, —I,(5) —CO—OH, (6) —C≡N, (V) C₂-C₁₀ alkenyl optionally substituted withone, two or three substituents independently selected from the groupconsisting of C₁-C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁-C₆alkoxy, —O-phenyl, and —NR_(1-a)R_(1-b), (VI) C₂-C₁₀ alkynyl optionallysubstituted with one, two or three substituents independently selectedfrom the group consisting of C₁-C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH,—C≡N, —CF₃, C₁-C₆ alkoxy, —O-phenyl, and —NR_(1-a)R_(1-b), (VII) —(C₁-C₆alkyl)-O-(C₁-C₆ alkyl)-OH, (VIII) —CH₂—NH—CH₂—CH(—O—CH₂—CH₃)₂, (IX)—(CH₂)₀₋₆—C (═NR_(1-a)) (NR_(1-a)R_(1-b)); where R_(N) is (I)R_(N-1)—X_(N)— where X_(N) is —CO—, and where R_(N-1) is selected fromthe group consisting of: (A) phenyl, which is optionally substitutedwith one, two or three of the following substituents which can be thesame or different and are: (1) C₁-C₆ alkyl, optionally substituted withone, two or three substituents selected from the group consisting ofC₁-C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and—NR_(1-a)R_(1-b), wherein R_(1-a) and R_(1-b) at each occurrence areindependently H or C₁-C₆ alkyl, (2) —OH, (3) —NO₂, (4) —F, —Cl, —Br, —I,(5) —CO₂H, (6) —C≡N, (7) —(CH₂)₀₋₄—CO—NR_(N-2)R_(N-3) where R_(N-2) andR_(N-3) are the same or different and are selected from the groupconsisting of: (a) —H, (b) —C₁-C₈ alkyl optionally substituted with onesubstituent selected from the group consisting of: (i) —OH, (ii) —NH₂,(iii) phenyl, (c) —C₁-C₈ alkyl optionally substituted with 1, 2, or 3groups that are independently —F, —Cl, —Br, or —I, (d) —C₃-C₈cycloalkyl, (e) —(C₁-C₂ alkyl)-(C₃-C₈ cycloalkyl), (f) —(C₁-C₆alkyl)-O-(C₁-C₃ alkyl), (g) —C₂-C₆ alkenyl, (h) —C₂-C₆ alkynyl, (i)—C₁-C₆ alkyl chain with one double bond and one triple bond, (j)—R_(1-aryl), wherein R_(1-aryl) at each occurrence is independentlyphenyl, naphthyl, indanyl, indenyl, dihydronaphthyl, or tetralinyl eachof which is optionally substituted with 1, 2, 3, or 4 groups that areindependently: (i) C₁-C₆ alkyl optionally substituted with one, two orthree substituents independently selected from the group consisting ofC₁-C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH, —NR_(1-a)R_(1-b), —C≡N, —CF₃,and C₁-C₃ alkoxy, (ii) C₂-C₆ alkenyl with one or two double bonds,optionally substituted with one, two or three substituents independentlyselected from the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃,C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b), (iii) C₂-C₆ alkynyl optionallysubstituted with 1, 2, or 3 groups that are independently selected fromthe group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and—NR_(1-a)R_(1-b), (iv) —F, Cl, —Br and —I, (v) —C₁-C₆ alkoxy optionallysubstituted with 1, 2, or 3 —F, (vi) —NR_(N-2)R_(N-3), (vii) —OH, (viii)—C≡N, (ix) C₃-C₇ cycloalkyl, optionally substituted with 1, 2, or 3groups that are selected from the group consisting of —F, —Cl, —OH, —SH,—C≡N, —CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b), (x) —CO-(C₁-C₄ alkyl),(xi) —SO₂—NR_(1-a)R_(1-b), (xii) —CO—NR_(1-a)R_(1-b), or (xiii)—SO₂-(C₁-C₄ alkyl), (k) —R_(1-heteroaryl), wherein R_(1-heteroaryl) ateach occurrence is independently selected from the group consisting ofpyridinyl, pyrimidinyl, quinolinyl, benzothienyl, indolyl, indolinyl,pryidazinyl, pyrazinyl, isoindolyl, isoquinolyl, quinazolinyl,quinoxalinyl, phthalazinyl, imidazolyl, isoxazolyl, pyrazolyl, oxazolyl,thiazolyl, indolizinyl, indazolyl, benzothiazolyl, benzimidazolyl,benzofuranyl, furanyl, thienyl, pyrrolyl, oxadiazolyl, thiadiazolyl,triazolyl, tetrazolyl, oxazolopyridinyl, imidazopyridinyl, isothiazolyl,naphthyridinyl, cinnolinyl, carbazolyl, beta-carbolinyl, isochromanyl,chromanyl, tetrahydroisoquinolinyl, isoindolinyl,isobenzotetrahydrofuranyl, isobenzotetrahydrothienyl, isobenzothienyl,benzoxazolyl, pyridopyridinyl, benzotetrahydrofuranyl,benzotetrahydrothienyl, purinyl, benzodioxolyl, triazinyl, phenoxazinyl,phenothiazinyl, pteridinyl, benzothiazolyl, imidazopyridinyl,imidazothiazolyl, dihydrobenzisoxazinyl, benzisoxazinyl, benzoxazinyl,dihydrobenzisothiazinyl, benzopyranyl, benzothiopyranyl, coumarinyl,isocoumarinyl, chromonyl, chromanonyl, pyridinyl-N-oxide,tetrahydroquinolinyl, dihydroquinolinyl, dihydroquinolinonyl,dihydroisoquinolinonyl, dihydrocoumarinyl, dihydroisocoumarinyl,isoindolinonyl, benzodioxanyl, benzoxazolinonyl, pyrrolyl N-oxide,pyrimidinyl N-oxide, pyridazinyl N-oxide, pyrazinyl N-oxide, quinolinylN-oxide, indolyl N-oxide, indolinyl N-oxide, isoquinolyl N-oxide,quinazolinyl N-oxide, quinoxalinyl N-oxide, phthalazinyl N-oxide,imidazolyl N-oxide, isoxazolyl N-oxide, oxazolyl N-oxide, thiazolylN-oxide, indolizinyl N-oxide, indazolyl N-oxide, benzothiazolyl N-oxide,benzimidazolyl N-oxide, pyrrolyl N-oxide, oxadiazolyl N-oxide,thiadiazolyl N-oxide, triazolyl N-oxide, tetrazolyl N-oxide,benzothiopyranyl S-oxide, and benzothiopyranyl S,S-dioxide, where theR_(1-heteroaryl) group is optionally substituted with 1, 2, 3, or 4groups that are independently: (i) C₁-C₆ alkyl optionally substitutedwith 1, 2, or 3 groups independently selected from the group consistingof C₁-C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH, —NR_(1-a)R_(1-b), —C≡N,—CF₃, and C₁-C₃ alkoxy, (ii) C₂-C₆ alkenyl optionally substituted with1, 2, or 3 groups that are independently —F, —Cl, —OH, —SH, —C≡N, —CF₃,C₁-C₃ alkoxy, or —NR_(1-a)R_(1-b), (iii) C₂-C₆ alkynyl optionallysubstituted with 1, 2, or 3 groups that are independently —F, —Cl, —OH,—SH, —C≡N, —CF₃, C₁-C₃ alkoxy, or —NR_(1-a)R_(1-b), (iv) —F, —Cl, —Brand —I, (v) —C₁-C₆ alkoxy optionally substituted with one, two, or three—F, (vi) —(CH₂)₀₋₄—NR_(N-2)R_(N-3), (vii) —OH, (viii) —C≡N, (ix)(CH₂)₀₋₄—C₃-C₇ cycloalkyl, optionally substituted with 1, 2, or 3 groupsthat are independently selected from the group consisting of —F, —Cl,—OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b), (x)(CH₂)₀₋₄—CO-(C₁-C₆ alkyl), (xi) (CH₂)₀₋₄—SO₂—NR_(N-2)R_(N-3), (xii)(CH₂)₀₋₄—CO—NR_(N-2)R_(N-3), (xiii) (CH₂)₀₋₄—SO₂-(C₁-C₆ alkyl), (xiv)(CH₂)₀₋₄—N(R_(N-2))—SO₂—, and (xv) (CH₂)₀₋₄—N (R_(N-2))—C(O)—, (1)—R_(1-heterocyle), wherein R_(1-heterocycle) at each occurrence isindependently selected from the group consisting of morpholinyl,thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S,S-dioxide,piperazinyl, homopiperazinyl, pyrrolidinyl, pyrrolinyl,tetrahydropyranyl, piperidinyl, tetrahydrofuranyl, tetrahydrothienyl,homopiperidinyl, homomorpholinyl, homothiomorpholinyl,homothiomorpholinyl S,S-dioxide, oxazolidinonyl, dihydropyrazolyl,dihydropyrrolyl, dihydropyrazinyl, dihydropyridinyl, dihydropyrimidinyl,dihydrofuryl, dihydropyranyl, tetrahydrothienyl S-oxide,tetrahydrothienyl S,S-dioxide, and homothiomorpholinyl S-oxide, wherethe R_(1-heterocycle) group is bonded by any atom of the parentR_(1-heterocycle) group substituted by hydrogen such that the new bondto the R_(1-heterocycle) group replaces the hydrogen atom and its bond,where heterocycle is optionally substituted with 1, 2, 3, or 4 groupsthat are independently: (a) C₁-C₆ alkyl optionally substituted with one,two or three substituents independently selected from the groupconsisting of C₁-C₃ alkyl, halogen, —OH, —SH, —NR_(1-a)R_(1-b) —C≡N,—CF₃, and C₁-C₃ alkoxy, (b) C₂-C₆ alkenyl with one or two double bonds,optionally substituted with one, two or three substituents independentlyselected from the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃,C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b p4 (c) C) ₂-C₆ alkynyl with one or twotriple bonds, optionally substituted with one, two or three substituentsindependently selected from the group consisting of —F, —Cl, —OH, —SH,—C≡N, —CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b) (d) halogen, (e) C₁-C₆alkoxy, (f) —C₁-C₆ alkoxy optionally substituted with one, two, or three—F, (g) —NR_(N-2)R_(N-3), (h) —OH, (i) —C≡N, (j) (CH₂)₀₋₄-(C₃-C₈cycloalkyl), optionally substituted with 1, 2, or 3 groups independentlyselected from the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃,C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b), (k) —(CH₂)₀₋₄—CO-(C₁-C₄ alkyl), (l)—(CH₂)₀₋₄—SO₂—NR_(1-a)R_(1-b), (m) —(CH₂)₀₋₄—CO—NR_(1-a)R_(1-b), (n)—(CH₂)₀₋₄—SO₂-(C₁-C₆ alkyl), and (o) ═O, (p) —(CH₂)₀₋₄—N (R_(N-2))—SO₂—(q) —(CH₂)₀₋₄—N (R_(N-2))—C (O)— (8) —(CH₂)₀₋₄—CO-(C₁-C₁₂ alkyl), (9)—(CH₂)₀₋₄—CO-(C₂-C₁₂ alkenyl), (10) —(CH₂)₀₋₄—CO-(C₂-C₁₂ alkynyl), (11)—(CH₂)₀₋₄—CO-(C₃-C₈ cycloalkyl), (12) —(CH₂)₀₋₄—CO—R_(1-aryl), (13)—(CH₂)₀₋₄—CO—R_(1-heteroaryl), (14) —(CH₂)₀₋₄—CO—R_(1-heterocycle), (15)—(CH₂)₀₋₄—CO—R_(N-4) wherein R_(N-4) is selected from the groupconsisting of phenyl, morpholinyl, thiomorpholinyl, piperazinyl,piperidinyl, homomorpholinyl, homothiomorpholinyl, homothiomorpholinylS-oxide, homothiomorpholinyl S,S-dioxide, pyrrolinyl, thienyl,pyrazolyl, pyridyl N-oxide, oxazolyl, thiazolyl, imidazolyl, andpyrrolidinyl where each group is optionally substituted with one, two,three, or four groups that are independently C₁-C₆ alkyl, (16)—(CH₂)₀₋₄—CO—O—R_(N-5) where R_(N-5) is selected from the groupconsisting of: (a) C₁-C₆ alkyl, (b) —(CH₂)₀₋₂—(R_(1-aryl)) (c) C₂-C₆alkenyl, (d) C₂-C₆ alkynyl, (e) —(CH₂)₀₋₂—C₃-C₈ cycloalkyl, (f)—(CH₂)₀₋₂—(R_(1-heteroaryl)), and (g) —(CH₂)₀₋₂—(R_(1-heterocycle)),(17) —(CH₂)₀₋₄—SO₂—NR_(N-2)R_(N-3), (18) —(CH₂)₀₋₄—SO-(C₁-C₈ alkyl),(19) —(CH₂)₀₋₄—SO₂₋(C₁-C₁₂ alkyl), (20) —(CH₂)₀₋₄—SO₂-(C₃-C₈cycloalkyl), (21) —(CH₂)₀₋₄—N(H or R_(N-5))—CO—O—R_(N-5), (22)—(CH₂)₀₋₄—N(H or R_(N-5))—CO—N (R_(N-5))₂, (23)—(CH₂)₀₋₄—N—CS—N(R_(N-5))₂, (24) —(CH₂)₀₋₄—N (H or R_(N-5))—CO—R_(N-2),(25) —(CH₂)₀₋₄—NR_(N-2)R_(N-3), (26) —(CH₂)₀₋₄—R_(N-4), (27)—(CH₂)₀₋₄—O—CO-(C₁-C₆ alkyl), (28) —(CH₂)₀₋₄—O—P(O)—(OR₁₀₀)₂ whereinR₁₀₀ at each occurrence is independently —H or C₁-C₄ alkyl, (29)—(CH₂)₀₋₄—O—CO—N(R_(N-5))₂, (30) —(CH₂)₀₋₄—O—CS—N (R_(N-5))₂, (31)—(CH₂)₀₋₄—O—(R_(N-5)), (32) —(CH₂)₀₋₄—O—(R_(N-5))—COOH, (33)—(CH₂)₀₋₄—S—(R_(N-5)), (34) —(CH₂)₀₋₄—O-(C₁-C₆ alkyl optionallysubstituted with one, two, three, four, or five of —F), (35) C₃-C₈cycloalkyl, (36) C₂-C₆ alkenyl optionally substituted with C₁-C₃ alkyl,—F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, or—NR_(1-a)R_(1-b), (37) C₂-C₆ alkynyl optionally substituted with C₁-C₃alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, or—NR_(1-a)R_(1-b), (38) —(CH₂)₀₋₄—N(H or R_(N-5))—SO₂—R_(N-2), (39)—(CH₂)₁₋₄-(C₃-C₈ cycloalkyl), (B) —R_(N-heteroaryl) whereR_(N-heteroaryl) is selected from the group consisting of pyridinyl,indolyl, indolinyl, isoindolyl, imidazolyl, isoxazolyl, oxazolyl,thiazolyl, indolizinyl and isochromanyl, where the R_(N-heteroaryl)group is bonded by any atom of the parent R_(N-heteroaryl) groupsubstituted by hydrogen such that the new bond to the R_(N-heteroaryl)group replaces the hydrogen atom and its bond, where heteroaryl isoptionally substituted with one, two, three, or four of: (1) C₁-C₆alkyl, optionally substituted with one, two or three substituentsselected from the group consisting of C₁-C₃ alkyl, —F, —Cl, —Br, —I,—OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b), (2) —OH, (3)—NO₂, (4) —F, —Cl, —Br, —I, (5) —CO₂H, (6) —C≡N, (7)—(CH₂)₀₋₄—CO—NR_(N-2)R_(N-3), (8) —(CH₂)₀₋₄—CO-(C₁-C₁₂ alkyl), (9)—(CH₂)₀₋₄—CO-(C₂-C₁₂ alkenyl), (10) —(CH₂)₀₋₄—CO-(C₂-C₁₂ alkynyl), (11)—(CH₂)₀₋₄—CO-(C₃-C₈ cycloalkyl), (12) —(CH₂)₀₋₄—CO—R_(1-aryl), (13)—(CH₂)₀₋₄—CO—R_(1-heteroaryl), (14) —(CH₂)₀₋₄—CO—R_(1-heterocycle), (15)—(CH₂)₀₋₄—CO—R_(N-4) (16) —(CH₂)₀₋₄—CO—O—R_(N-5) (17)—(CH₂)₀₋₄—SO₂—NR_(N-2)R_(N-3), (18) —(CH₂)₀₋₄—SO-(C₁-C₈ alkyl), (19)—(CH₂)₀₋₄—SO₂-(C₁-C₁₂ alkyl), (20) —(CH₂)₀₋₄—SO₂-(C₃-C₈ cycloalkyl),(21) —(CH₂)₀₋₄—N(H or R_(N-5))—CO—O—R_(N-5), (22) —(CH₂)₀₋₄—N(H orR_(N-5))—CO—N (R_(N-5))₂,, (23) —(CH₂)₀₋₄—N—CS—N(R_(N-5))₂, (24)—(CH₂)₀₋₄—N(—H or R_(N-5))—CO—R_(N-2), (25) —(CH₂)₀₋₄—NR_(N-2)R_(N-3),(26) —(CH₂)₀₋₄—R_(N-4), (27) —(CH₂)₀₋₄—O—CO-(C₁-C₆ alkyl), (28)—(CH₂)₀₋₄—O—P(O)—(OR₁₀₀)₂, (29) —(CH₂)₀₋₄—O—CO—N(R_(N-5))₂, (30)—(CH₂)₀₋₄—O—CS—N(R_(N-5))₂, (31) —(CH₂)₀₋₄—O—(R_(N-5)), (32)—(CH₂)₀₋₄—O—(R_(N-5))—COOH, (33) —(CH₂)₀₋₄—S—(R_(N-5)), (34)—(CH₂)₀₋₄—O-(C₁-C₆ alkyl optionally substituted with one, two, three,four, or five of —F), (35) C₃-C₈ cycloalkyl, (36) C₂-C₆ alkenyloptionally substituted with C₁-C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH,—C≡N, —CF₃, C₁-C₃ alkoxy, or —NR_(1-a)R_(1-b), (37) C₂-C₆ alkynyloptionally substituted with C₁-C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH,—C≡N, —CF₃, C₁-C₃ alkoxy, or —NR_(1-a)R_(1-b), (38) —(CH₂)₀₋₄—N(—H orR_(N-5))—SO₂—R_(N-2), (39) —(CH₂)₁₋₄—C₃-C₈ cycloalkyl, (C)R_(N-aryl)—W—R_(N-aryl), (D) R_(N-aryl)—W—R_(N-heteroaryl), (E)R_(N-aryl)—W—R_(1-heterocycle), , (F) R_(N-heteroaryl)—W—R_(N-aryl), (G)R_(N-heteroaryl)—W—R_(N-heteroaryl), (H)R_(N-heteroaryl)—W—R_(N-1-heterocycle), (I)R_(N-heterocycle)—W—R_(N-aryl), (J)R_(N-heterocycle)—W—R_(N-heteroaryl), (K)R_(N-heterocycle)—W—R_(N-1-heterocycle), where W is (25) —(CH₂)₁₋₄—,(26) —O—, (27) —S(O)₀₋₂—, (28) —N(R_(N-5))—, (29) —CO—; or (30) a bond;(II) —CO-(C₁-C₆ alkyl)-M-(C₁-C₆ alkyl), where M is S, SO or SO₂, andwherein each alkyl is unsubstituted or substituted with one, two, orthree of substituents independently selected from the group consistingof: (A) —NH—CO-(C₁-C₆ alkyl), (B) —NH—CO—O—R_(N-8), (C)—NR_(N-2)R_(N-3); where R₁ is —(CH₂)_(n1)-phenyl, where n₁ is zero orone, and which is optionally substituted with one, two, three or four ofthe following substituents on the phenyl ring: (A) C₁-C₆ alkyloptionally substituted with one, two or three substituents selected fromthe group consisting of C₁-C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N,—CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b), (B) C₂-C₆ alkenyl with one ortwo double bonds, optionally substituted with one, two or threesubstituents selected from the group consisting of —F, —Cl, —OH, —SH,—C≡N, —CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b), (C) C₂-C₆ alkynyl withone or two triple bonds, optionally substituted with one, two or threesubstituents selected from the group consisting of —F, —Cl, —OH, —SH,—C≡N, —CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b), (D) —F, Cl, —Br or —I,(F) —C₁-C₆ alkoxy optionally substituted with one, two or three of —F,(G) —NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) are as defined below, (H)—OH, (I) —C≡N, (J) C₃-C₇ cycloalkyl, optionally substituted with one,two or three substituents selected from the group consisting of —F, —Cl,—OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b), (K) —CO-(C₁-C₄alkyl), (L) —SO₂—NR_(1-a)R_(1-b), (M) —CO—NR_(1-a)R_(1-b), (N)—SO₂-(C₁-C₄ alkyl); and where R₂ is (I) —(Z)—C₁-C₆ alkyl, where Z is abond, —C(O)—, —CO₂— or —SO₂—, wherein the alkyl group is optionallysubstituted with one, two or three substituents selected from the groupconsisting of C₁-C₃ alkyl, C₁-C₇ alkyl (optionally substituted withC₁-C₃ alkyl and C₁-C₃ alkoxy), —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃,C₁-C₃ alkoxy, —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) areindependently —H or C₁-C₆ alkyl, and —OC═O NR_(1-a)R_(1-b), (II)—(Z)—CH₂—S(O)₀₋₂-(C₁-C₆ alkyl), (III) —(Z)—CH₂—CH₂—S(O)₀₋₂-(C₁-C₆alkyl), (IV) —(Z)—C₂-C₆ alkenyl with one or two double bonds, optionallysubstituted with one, two or three substituents selected from the groupconsisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and—NR_(1-a)R_(1-b), (V) —(Z)—C₂-C₆ alkynyl with one or two triple bonds,optionally substituted with one, two or three substituents selected fromthe group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and—NR_(1-a)R_(1-b), (VI) —(Z)—(CH₂)_(n1)—(R_(1-aryl)), where Z is a bond,CO, CO₂ or SO₂, where n₁ is zero or one and where R_(1-aryl) is phenyl,1-naphthyl, 2-naphthyl and indanyl, indenyl, dihydronaphthalyl, ortetralinyl optionally substituted with one, two, three or four of thefollowing substituents on the aryl ring: (A) C₁-C₆ alkyl optionallysubstituted with one, two or three substituents selected from the groupconsisting of C₁-C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁-C₃alkoxy, and —NR_(1-a)R_(1-b), (B) C₂-C₆ alkenyl with one or two doublebonds, optionally substituted with one, two or three substituentsselected from the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃,C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b), (C) C₂-C₆ alkynyl with one or twotriple bonds, optionally substituted with one, two or three substituentsselected from the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃,C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b), (D) —F, Cl, —Br or —I, (F) —C₁-C₆alkoxy optionally substituted with one, two or three of —F, (G)—NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) are as defined below, (H)—OH, (I) —C≡N, (J) C₃-C₇ cycloalkyl, optionally substituted with one,two or three substituents selected from the group consisting of —F, —Cl,—OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b), (K) —CO-(C₁-C₄alkyl), (L) —SO₂—NR_(1-a)R_(1-b), (M) —CO—NR_(1-a)R_(1-b), (N)—SO₂-(C₁-C₄ alkyl), (VII) —(Z)—(CH₂)_(n1)—(R_(1-heteroaryl)) where n₁ isas defined above and where R_(1-heteroaryl) is selected from the groupconsisting of: pyridinyl, pyrimidinyl, quinolinyl, benzothienyl,indolyl, indolinyl, pryidazinyl, pyrazinyl, isoindolyl, isoquinolyl,quinazolinyl, quinoxalinyl, phthalazinyl, imidazolyl, isoxazolyl,pyrazolyl, oxazolyl, thiazolyl, indolizinyl, indazolyl, benzothiazolyl,benzimidazolyl, benzofuranyl, furanyl, thienyl, pyrrolyl, oxadiazolyl,thiadiazolyl, triazolyl, tetrazolyl, oxazolopyridinyl, imidazopyridinyl,isothiazolyl, naphthyridinyl, cinnolinyl, carbazolyl, beta-carbolinyl,isochromanyl, chromanyl, tetrahydroisoquinolinyl, isoindolinyl,isobenzotetrahydrofuranyl, isobenzotetrahydrothienyl, isobenzothienyl,benzoxazolyl, pyridopyridinyl, benzotetrahydrofuranyl,benzotetrahydrothienyl, purinyl, benzodioxolyl, triazinyl, phenoxazinyl,phenothiazinyl, pteridinyl, benzothiazolyl, imidazopyridinyl,imidazothiazolyl, dihydrobenzisoxazinyl, benzisoxazinyl, benzoxazinyl,dihydrobenzisothiazinyl, benzopyranyl, benzothiopyranyl, coumarinyl,isocoumarinyl, chromonyl, chromanonyl, pyridinyl-N-oxide,tetrahydroquinolinyl, dihydroquinolinyl, dihydroquinolinonyl,dihydroisoquinolinonyl, dihydrocoumarinyl, dihydroisocoumarinyl,isoindolinonyl, benzodioxanyl, benzoxazolinonyl, pyrrolyl N-oxide,pyrimidinyl N-oxide, pyridazinyl N-oxide, pyrazinyl N-oxide, quinolinylN-oxide, indolyl N-oxide, indolinyl N-oxide, isoquinolyl N-oxide,quinazolinyl N-oxide, quinoxalinyl N-oxide, phthalazinyl N-oxide,imidazolyl N-oxide, isoxazolyl N-oxide, oxazolyl N-oxide, thiazolylN-oxide, indolizinyl N-oxide, indazolyl N-oxide, benzothiazolyl N-oxide,benzimidazolyl N-oxide, pyrrolyl N-oxide, oxadiazolyl N-oxide,thiadiazolyl N-oxide, triazolyl N-oxide, tetrazolyl N-oxide,benzothiopyranyl S-oxide, benzothiopyranyl S,S-dioxide, where theR_(1-heteroaryl) group is bonded to —(CH₂)_(n1)— by any ring atom of theparent R_(N-heteroaryl) group substituted by hydrogen such that the newbond to the R_(1-heteroaryl) group replaces the hydrogen atom and itsbond, where heteroaryl is optionally substituted with one, two, three orfour of: (1) C₁-C₆ alkyl optionally substituted with one, two or threesubstituents selected from the group consisting of C₁-C₃ alkyl, —F, —Cl,—Br, —I, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b), (2)C₂-C₆ alkenyl with one or two double bonds, optionally substituted withone, two or three substituents selected from the group consisting of —F,—Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b), (3) C₂-C₆alkynyl with one or two triple bonds, optionally substituted with one,two or three substituents selected from the group consisting of —F, —Cl,—OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b), (4) —F, Cl,—Br or —I, (6) —C₁-C₆ alkoxy optionally substituted with one, two, orthree of —F, (7) —NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) are asdefined below, (8) —OH, (9) —C≡N, (10) C₃-C₇ cycloalkyl, optionallysubstituted with one, two or three substituents selected from the groupconsisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and—NR_(1-a)R_(1-b), (11) —CO-(C₁-C₄ alkyl), (12) —SO₂—NR_(1-a)R_(1-b),(13) —CO—NR_(1-a)R_(1-b), or (14) —SO₂-(C₁-C₄ alkyl), with the provisothat when n₁ is zero R_(1-heteroaryl) is not bonded to the carbon chainby nitrogen, or (VIII) —(Z)—(CH₂)_(n1)—(R_(1-heterocycle)) where n₁ isas defined above and R_(1-heterocycle) is selected from the groupconsisting of: morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide,thiomorpholinyl S,S-dioxide, piperazinyl, homopiperazinyl, pyrrolidinyl,pyrrolinyl, tetrahydropyranyl, piperidinyl, tetrahydrofuranyl,tetrahydrothienyl, homopiperidinyl, homomorpholinyl, homomorpholinylS-oxide, homothiomorpholinyl S,S-dioxide, oxazolidinonyl,dihydropyrazolyl, dihydropyrrolyl dihydropyrazinyl dihydropyridinyldihydropyrimidinyl, dihydrofuryl, dihydropyranyl, tetrahydrothienylS-oxide, tetrahydrothienyl S,S-dioxide, homothiomorpholinyl S-oxide,where the R_(1-heterocycle) group is bonded by any atom of the parentR_(1-heterocycle) group substituted by hydrogen such that the new bondto the R_(1-heterocycle) group replaces the hydrogen atom and its bond,where heterocycle is optionally substituted with one, two, three orfour: (1) C₁-C₆ alkyl optionally substituted with one, two or threesubstituents selected from the group consisting of C₁-C₃ alkyl, —F, —Cl,—Br, —I, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b), (2)C₂-C₆ alkenyl with one or two double bonds, optionally substituted withone, two or three substituents selected from the group consisting of —F,—Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b), (3) C₂-C₆alkynyl with one or two triple bonds, optionally substituted with one,two or three substituents selected from the group consisting of —F, —Cl,—OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b), (4) —F, Cl,—Br, or —I, (5) C₁-C₆ alkoxy, (6) —C₁-C₆ alkoxy optionally substitutedwith one, two, or three —F, (7) —NR_(N-2)R_(N-3) where R_(N-2) andR_(N-3) are as defined below, (8) —OH, (9) —C≡N, (10) C₃-C₇ cycloalkyl,optionally substituted with one, two or three substituents selected fromthe group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and—NR_(1-a)R_(1-b), (11) —CO-(C₁-C₄ alkyl) (12) —SO₂—NR_(1-a)R_(1-b), (13)—CO—NR_(1-a)R_(1-b), (14) —SO₂-(C_(l)-C₄ alkyl), (15) ═O, with theproviso that when n₁ is zero R_(1-heterocycle) is not bonded to thecarbon chain by nitrogen; and where R₂₀ is H or C₁₋₆ alkyl or alkenyl.